US10781260B2 - Anti-OX40 binding proteins - Google Patents
Anti-OX40 binding proteins Download PDFInfo
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- US10781260B2 US10781260B2 US16/323,968 US201716323968A US10781260B2 US 10781260 B2 US10781260 B2 US 10781260B2 US 201716323968 A US201716323968 A US 201716323968A US 10781260 B2 US10781260 B2 US 10781260B2
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/75—Agonist effect on antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- OX40 (also known as CD 134, TNFRSF4, ACT35 or TXGP1L) is a member of the TNF receptor superfamily, which includes 4-1BB, CD27, CD30 and CD40.
- the extracellular ligand binding domain of OX40 is composed of 3 full cysteine-rich domains (CRDs) and a partial, fourth C-terminal CRD (Bodmer et al, 2002 , Trends Biochem. Sci., 27, 19-26).
- the ligand for OX40, OX40L is a member of the TNF family and is expressed on activated antigen presenting cells (APC), including B cells, macrophages, endothelial cells and dendritic cells (DC).
- APC activated antigen presenting cells
- DC dendritic cells
- OX40 is a membrane-bound receptor; however a soluble isoform has also been detected (Taylor and Schwarz, 2001 , J. Immunol. Methods, 255, 67-72). OX40 is not expressed on resting T cells, but is transiently expressed on activated T cells after ligation of the T cell receptor (TCR).
- TCR T cell receptor
- OX40 is a major costimulatory receptor with sequential engagement of CD28 and OX40 resulting in optimal T cell proliferation and survival. Ligation of OX40 on activated T cells leads to enhanced cytokine production and proliferation of both CD4+ and CD8+ T cells (Gramaglia et al., 2000 , J. Immunol, 165, 3043-3050, Bansal-Pakala et al., 2004 , J. Immunol., 172, 4821-425) and can contribute to both ongoing Th1 and Th2 responses (Gramaglia et al., 1998 , J. Immunol., 161, 6510-6517, Arestides et al, 2002 , Eur. J. Immunol. 32, 2874-2880). OX40 costimulation prolongs T cell survival beyond the initial effector phase of the immune response and increases the number of memory T cells through inhibition of effector T cell death.
- Tumor cells commonly ‘escape’ the immune system by induction of an active immune tolerance largely mediated by regulatory T lymphocytes (Tregs et al. Immunol Rev. 2011; 241:104-118). Therefore, the balance between effector (i.e., direct or indirect eradication of tumor cells) T lymphocytes (Teffs) and tolerogenic (i.e., suppression of Teffs effector function and survival) Tregs appears to be important for effective anti-tumor immunotherapy. In other words, an effective anti-tumor immune response can be obtained by enhancing effector function of tumor-specific Teffs and/or by attenuating suppressive function of tumor-specific Tregs. A key receptor that has been shown to mediate these responses is OX40 (CD134). (Sugamura et al., Nature Rev. Imm. 2004; 4: 420-431).
- mouse CD134 receptor by either soluble mouse OX40 ligand (OX40L)-immunoglobulin fusion proteins or mouse OX40L mimetics, such as anti-mouse CD134-specific antibodies
- OX40L soluble mouse OX40 ligand
- mouse OX40L mimetics such as anti-mouse CD134-specific antibodies
- tumor-bearing mice enhances anti-tumor immunity, leads to tumor-free survival in mouse models of various murine malignant tumor cell lines, e.g., lymphoma, melanoma, sarcoma, colon cancer, breast cancer, and glioma (Sugamura et al. Nature Rev. Imm. 2004; 4:420631). Al-Shamkhani et al. ( Eur. J. Chem.
- the invention provides antibodies that specifically bind to OX40, including human OX40.
- the invention features an isolated anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising a heavy chain CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID Nos: 49, 50 and 51; SEQ ID Nos: 55, 56 and 57; SEQ ID Nos: 61, 62 and 63; SEQ ID Nos: 67, 68 and 69; SEQ ID Nos: 73, 74 and 75; SEQ ID Nos: 79, 80 and 81; SEQ ID Nos: 85, 86 and 87; SEQ ID Nos: 91, 92 and 93; SEQ ID Nos: 103, 104 and 105; SEQ ID Nos: 109, 110 and 111; SEQ ID Nos: 118, 119 and 120; SEQ ID Nos: 133, 134 and 135; SEQ ID Nos: 139, 140 and 141; SEQ ID Nos: 148
- a light chain variable domain comprising a light chain CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID Nos: 52, 53 and 54; SEQ ID Nos: 58, 59 and 60; SEQ ID Nos: 64, 65 and 66; SEQ ID Nos: 70, 71 and 72; SEQ ID Nos: 76, 77 and 78; SEQ ID Nos: 82, 83 and 84; SEQ ID Nos: 88, 89 and 90; SEQ ID Nos: 94, 95 and 96; SEQ ID Nos: 97, 98 and 99; SEQ ID Nos: 100, 101 and 102; SEQ ID Nos: 106, 107 and 108; SEQ ID Nos: 112, 113 and 114; SEQ ID Nos: 115, 116 and 117; SEQ ID Nos: 121, 122 and 123;
- the heavy chain variable domain comprises an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO.
- SEQ ID NO. 42 SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201; and a light chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO.
- the heavy chain variable domain comprises an amino acid sequence that is at least 96% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO.
- the light chain variable domain comprises an amino acid sequence that is at least 96% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO.
- the heavy chain variable domain comprises an amino acid sequence that is at least 97% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO.
- the light chain variable domain comprises an amino acid sequence that is at least 97% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO.
- SEQ ID NO. 20 SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the heavy chain variable domain comprises an amino acid sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- 201 comprises a light chain variable domain comprising an amino acid sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO.
- the heavy chain variable domain comprises an amino acid sequence that is at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO.
- SEQ ID NO. 42 SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201; and comprises a light chain variable domain comprising an amino acid sequence that is at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO.
- the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO.
- SEQ ID NO. 29 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201; and comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO.
- SEQ ID NO. 30 SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention provides an isolated anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain CDR set/light chain CDR set selected from the group consisting of SEQ ID Nos: 49, 50 and 51/SEQ ID Nos: 52, 53 and 54; SEQ ID Nos: 55, 56 and 57/SEQ ID Nos: 58, 59 and 60; SEQ ID Nos: 61, 62 and 63/SEQ ID Nos: 64, 65 and 66; SEQ ID Nos: 67, 68 and 69/SEQ ID Nos: 70, 71 and 72; SEQ ID Nos: 73, 74 and 75/SEQ ID Nos: 76, 77 and 78; SEQ ID Nos: 79, 80 and 81/SEQ ID Nos: 82, 83 and 84; SEQ ID Nos: 85, 86 and 87/SEQ ID Nos: 88, 89 and 90; SEQ ID Nos: 91, 92 and
- the invention features an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- a light chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention features an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising an amino acid sequence that is at least 96% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- a light chain variable domain comprising an amino acid sequence that is at least 96% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention features an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising an amino acid sequence that is at least 97% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- a light chain variable domain comprising an amino acid sequence that is at least 97% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention features an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising an amino acid sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- a light chain variable domain comprising an amino acid sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention features an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising an amino acid sequence that is at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- SEQ ID NO. 2 SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention features an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the antibody, or antigen-binding fragment thereof has a K D of at least 1 ⁇ 10 ⁇ 6 M.
- the antibody, or antigen-binding fragment thereof is an isolated human antibody.
- the anti-OX40 antibody is an IgG.
- the antibody is an IgG1, IgG2, IgG3 or an IgG4 isotype.
- the antigen-binding fragment is a Fab fragment or an scFv.
- the invention features a pharmaceutical composition
- a pharmaceutical composition comprising the anti-OX40 antibody, or antibody fragment thereof, of any one of the above aspects or embodiments, and a pharmaceutically acceptable carrier.
- the invention features a method for treating a subject having cancer, the method comprising administering an effective amount of the anti-OX40 antibody, or antigen-binding fragment thereof, of any one of the above aspects or embodiments to the subject.
- the cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, head and neck cancer, bladder cancer, melanoma, colorectal cancer, pancreatic cancer, lung cancer, leiomyoma, leiomyosarcoma, glioma, glioblastoma, esophageal cancer, liver cancer, kidney cancer, stomach cancer, colon cancer, cervical cancer, uterine cancer, liver cancer and a hematological cancer.
- the cancer is selected from the group consisting of B chronic lymphocytic leukemia (B-CLL), B and T acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), myeloproliferative disorder/neoplasm (MPDS), myelodysplasia syndrome, non-Hodgkin's lymphoma (NHL), including Burkitt's lymphoma (BL), Waldenstrom's Macroglobulinemia, mantle cell lymphoma, AIDS-related lymphoma, Hodgkin's Lymphoma (HL), T cell lymphoma (TCL), multiple myeloma (MM), plasma cell myeloma, plamocytoma, giant cell myeloma, heavy-chain myeloma, and light chain or Bence-J
- the invention features a method for treating a subject having an inflammatory disease, the method comprising administering an effective amount of the anti-OX40 antibody, or antigen-binding fragment thereof, of any one of the above aspects or embodiments to the subject.
- the inflammatory disease is selected from the group consisting of allergy, COPD, autoimmune disease, rheumatoid arthritis, asthma, graft versus host disease, Crohn's disease, ulcerative colitis, type-1 diabetes, multiple sclerosis, Systemic lupus erythematosis, lupus nephritis, Myasthenia Gravis, Grave's disease, transplant rejection, Wegener's granulomatosis, Henoch-Schonlein purpura, systemic sclerosis, and viral-induced lung inflammation.
- the invention features a method for treating a subject having an infection, the method comprising administering an effective amount of the anti-OX40 antibody, or antigen-binding fragment thereof, of any one of the above aspects or embodiments to the subject.
- the invention features a method for treating a disease requiring either stimulation of immune responses or suppression, the method comprising administering an effective amount of the anti-OX40 antibody, or antigen-binding fragment thereof, of any one of the above aspects or embodiments to the subject.
- the disease is selected from the group consisting of cancer, an inflammatory disease, and a viral infection.
- nucleic acids encoding the amino acid sequences disclosed herein, as well as methods of making the antibodies and fragments of the invention.
- FIG. 1 is a graph that shows the binding of anti-OX40 antibody clones on activated human T-cells measured by the percent CD3+OX40+ T cells.
- the anti-OX40 clones that were tested are shown on the x-axis. Secondary antibody alone was used as a negative control.
- a commercially available APC-labelled anti-human OX40 (clone Ber-ACT35) was used as positive control.
- FIG. 2A is a graph that shows the luciferase activity measured by relative light units (RLUs) for the control experimental conditions after 6 hours of stimulation.
- RLUs relative light units
- FIG. 2B is a graph that shows luciferase activity measured by RLUs for the anti-OX40 antibody clones tested after 6 hours of stimulation. Unstimulated cells and isotype control FeH3 antibody (Ctrl FeH3) are shown as negative controls. Soluble anti-Histidine+purified rhOX40L (rhOX40L+ ⁇ His) is shown as a positive control. The line bisecting the graph shows the negative control RLU levels as a reference. As shown in FIG. 2B , all of the OX40 clones showed an increase in RLUs over the negative control values. Clones 1C4, 4D7 1D9 and 1B2 showed the strongest NFkB activation (>50% of signal observed with purified rhOX40L+anti-His).
- FIG. 3A is a graph that shows the luciferase activity measured by relative light units (RLUs) for the control experimental conditions after ⁇ 15 hours of stimulation.
- RLUs relative light units
- FIG. 3B is a graph that shows luciferase activity measured by RLUs for the anti-OX40 antibody clones tested after ⁇ 15 hours of stimulation. Unstimulated cells and isotype control FeH3 antibody (Ctrl FeH3) are shown as negative controls. Soluble anti-Histidine+purified rhOX40L (rhOX40L+ ⁇ His) is shown as a positive control. The line bisecting the graph shows the negative control RLU levels as a reference. As shown in FIG. 3B , most of the OX40 clones showed an increase in RLUs over the negative control values. In particular clones 1A11, 1C4, 4D7, 1D9, 5C11, 2B4, 4D9, 3C10 and 1B2 were among the most active.
- FIG. 4A is a graph that shows the percentage of CD3+CD25+ activated T cells as measured by flow cytometry. Anti-CD3 alone and FeD2, an isotype control antibody, were used as negative controls. Anti-CD28 was used as a positive control. The line bisecting the graph shows the negative control levels of percentage of CD3+CD25+ activated T cells as a reference.
- FIG. 4B is a graph that shows the percentage of CD3+CD25+ activated T cells as measured by flow cytometry.
- the line bisecting the graph shows the negative control levels of percentage of CD3+CD25+ activated T cells as a reference.
- clones 2B4, 4D7, 2B3, 4G9 and 1B1 showed the most robust agonist activity.
- an “antigen binding protein” is a protein comprising a portion that binds to an antigen and, optionally, a scaffold or framework portion that allows the antigen binding portion to adopt a confirmation that promotes binding of the antigen binding protein to the antigen.
- antigen binding proteins include antibodies, antibody fragments (e.g., an antigen binding fragment of an antibody), antibody derivatives, and antibody analogs.
- the antigen binding protein can comprise, for example, an alternative protein scaffold or artificial scaffold with grafted CDRs or CDR derivatives.
- Such scaffolds include, but are not limited to, antibody-derived scaffolds comprising mutations introduced to, for example, stabilize the three-dimensional structure of the antigen binding protein as well as wholly synthetic scaffolds comprising, for example, a biocompatible polymer.
- PAMs peptide antibody mimetics
- antibody is synonymous with immunoglobulin and is to be understood as commonly known in the art.
- the basic antibody structural unit is a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
- the amino-terminal portion of each antibody chain includes a variable region that is primarily responsible for antigen recognition.
- the carboxy-terminal portion of each chain defines a constant region, e.g., responsible for effector function.
- Human light chains are classified as kappa or lambda light chains.
- Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
- the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 3 or more amino acids.
- variable regions of each heavy/light chain pair form the antigen binding site.
- the variable regions of antibody heavy and light chains exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. From N-terminus to C-terminus, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
- the assignment of amino acids to each domain is known in the art, including, for example, definitions as described in Kabat et al. in Sequences of Proteins of Immunological Interest, 5 th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991 (herein referred to as “Kabat numbering”).
- the CDR regions of an antibody can be determined according to Kabat numbering.
- intact antibody or “full length antibody” refer to an antibody composed of two identical antibody light chains and two identical antibody heavy chains that each contain an Fc region.
- an “antigen binding domain,” “antigen binding region,” or “antigen binding site” is a portion of an antigen binding protein that contains amino acid residues (or other moieties) that interact with an antigen and contribute to the antigen binding protein's specificity and affinity for the antigen. For an antibody that specifically binds to its antigen, this will include at least part of at least one of its CDR domains.
- An “epitope” is the portion of a molecule that is bound by an antigen binding protein (e.g., by an antibody).
- An epitope can comprise non-contiguous portions of the molecule (e.g., in a polypeptide, amino acid residues that are not contiguous in the polypeptide's primary sequence but that, in the context of the polypeptide's tertiary and quaternary structure, are near enough to each other to be bound by an antigen binding protein).
- the variable regions, particularly the CDRs, of an antibody interact with the epitope.
- Fc polypeptide includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing the hinge region that promotes dimerization also are included. Fusion proteins comprising Fc moieties (and oligomers formed therefrom) offer the advantage of facile purification by affinity chromatography over Protein A or Protein G columns.
- anti-OX40 antibody and “an antibody that binds to OX40” refer to an antibody that is capable of binding OX40 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting OX40, including human OX40.
- the term “monospecific”, as used herein, refers to an antibody, or antigen binding fragment thereof, that displays an affinity for one particular epitope.
- a bispecific antibody, or antigen-binding fragment thereof displays affinity for two different epitopes.
- the methods and compositions described herein are useful for intracellular delivery of a monospecific antibody, or antigen-binding fragment thereof.
- the anti-OX40 antibody, or antigen-binding fragment thereof, of the invention is monospecific.
- a “multi-specific antibody” is an antibody that recognizes more than one epitope on one or more antigens.
- a subclass of this type of antibody is a “bispecific antibody” which recognizes two distinct epitopes on the same or different antigens.
- an antibody specifically binds to an antigen (e.g., OX40) if it binds to the antigen with a dissociation constant K D of 10 ⁇ 5 M or less (e.g., 10 ⁇ 6 M or less, 10 ⁇ 7 M or less, 10 ⁇ 8 M or less, 10 ⁇ 9 M or less, or 10 ⁇ 10 M or less).
- K D dissociation constant
- human antibody refers to an antibody, or an antigen binding fragment of an antibody, comprising heavy and lights chains derived from human immunoglobulin sequences.
- Human antibodies may be identified in a variety of ways, examples of which are described below, including through the immunization with an antigen of interest of a mouse that is genetically modified to express antibodies derived from human heavy and/or light chain-encoding genes.
- a human antibody is made using recombinant methods such that the glycosylation pattern of the antibody is different than an antibody having the same sequence if it were to exist in nature.
- chimeric antibody refers to an antibody that contains one or more regions derived from a particular source or species, and one or more regions derived from a different source or species.
- humanized antibody refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and/or VL sequence has been altered to be more “human-like,” i.e., more similar to human germline variable sequences.
- a “humanized antibody” is an antibody or a variant, derivative, analog, or fragment thereof, which immunospecifically binds to an antigen of interest and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementary determining region (CDR) having substantially the amino acid sequence of a non-human antibody.
- FR framework
- CDR complementary determining region
- a “humanized antibody” refers to an antibody having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions. Generally, a humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non-human species antibody, e.g., a murine or chimeric antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and/or light chains of the non-human species antibody are mutated to produce the humanized antibody. Examples of how to make humanized antibodies may be found in U.S. Pat. Nos. 6,054,297, 5,886,152 and 5,877,293.
- antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
- antibody fragments include, but are not limited to, Fv, Fab, Fab′, Fab′-SH, F(ab′) 2 ; Fd; and Fv fragments, as well as dAb; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); polypeptides that contain at least a portion of an antibody that is sufficient to confer specific antigen binding to the polypeptide.
- Antigen binding portions of an antibody may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies.
- Antigen binding portions include, inter alia, Fab, Fab′, F(ab′)2, Fv, domain antibodies (dAbs), and complementarity determining region (CDR) fragments, chimeric antibodies, diabodies, triabodies, tetrabodies, and
- the antibody fragment is an scFv.
- a single-chain antibody is an antibody in which a V L and a V H region are joined via a linker (e.g., a synthetic sequence of amino acid residues) to form a continuous protein chain (see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883)).
- a Fab fragment is a monovalent fragment having the V L , V H , C L and C H1 domains; a F(ab′) 2 fragment is a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment has the V H and C H1 domains; an Fv fragment has the V L and V H domains of a single arm of an antibody; and a dAb fragment has a V H domain, a V L domain, or an antigen-binding fragment of a V H or V L domain (U.S. Pat. Nos.
- Diabodies are bivalent antibodies comprising two polypeptide chains, wherein each polypeptide chain comprises VH and VL domains joined by a linker that is too short to allow for pairing between two domains on the same chain, thus allowing each domain to pair with a complementary domain on another polypeptide chain (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-48, and Poljak et al., 1994, Structure 2:1121-23). If the two polypeptide chains of a diabody are identical, then a diabody resulting from their pairing will have two identical antigen binding sites. Polypeptide chains having different sequences can be used to make a diabody with two different antigen binding sites. Similarly, tribodies and tetrabodies are antibodies comprising three and four polypeptide chains, respectively, and forming three and four antigen binding sites, respectively, which can be the same or different.
- the “percent identity” or “percent homology” of two polynucleotide or two polypeptide sequences is determined by comparing the sequences using the GAP computer program (a part of the GCG Wisconsin Package, version 10.3 (Accelrys, San Diego, Calif.)) using its default parameters.
- nucleic acid molecules e.g., cDNA or genomic DNA
- RNA molecules e.g., mRNA
- analogs of the DNA or RNA generated using nucleotide analogs e.g., peptide nucleic acids and non-naturally occurring nucleotide analogs
- hybrids thereof e.g., peptide nucleic acids and non-naturally occurring nucleotide analogs
- the nucleic acid molecule can be single-stranded or double-stranded.
- the nucleic acid molecules of the invention comprise a contiguous open reading frame encoding an antibody, or a fragment thereof, as described herein.
- Two single-stranded polynucleotides are “the complement” of each other if their sequences can be aligned in an anti-parallel orientation such that every nucleotide in one polynucleotide is opposite its complementary nucleotide in the other polynucleotide, without the introduction of gaps, and without unpaired nucleotides at the 5′ or the 3′ end of either sequence.
- a polynucleotide is “complementary” to another polynucleotide if the two polynucleotides can hybridize to one another under moderately stringent conditions.
- a polynucleotide can be complementary to another polynucleotide without being its complement.
- a “vector” is a nucleic acid that can be used to introduce another nucleic acid linked to it into a cell.
- a “plasmid” refers to a linear or circular double stranded DNA molecule into which additional nucleic acid segments can be ligated.
- a viral vector e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses
- certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors comprising a bacterial origin of replication and episomal mammalian vectors).
- vectors e.g., non-episomal mammalian vectors
- An “expression vector” is a type of vector that can direct the expression of a chosen polynucleotide.
- a nucleotide sequence is “operably linked” to a regulatory sequence if the regulatory sequence affects the expression (e.g., the level, timing, or location of expression) of the nucleotide sequence.
- a “regulatory sequence” is a nucleic acid that affects the expression (e.g., the level, timing, or location of expression) of a nucleic acid to which it is operably linked.
- the regulatory sequence can, for example, exert its effects directly on the regulated nucleic acid, or through the action of one or more other molecules (e.g., polypeptides that bind to the regulatory sequence and/or the nucleic acid).
- Examples of regulatory sequences include promoters, enhancers and other expression control elements (e.g., polyadenylation signals).
- a “host cell” is a cell that can be used to express a nucleic acid, e.g., a nucleic acid of the invention.
- a host cell can be a prokaryote, for example, E. coli , or it can be a eukaryote, for example, a single-celled eukaryote (e.g., a yeast or other fungus), a plant cell (e.g., a tobacco or tomato plant cell), an animal cell (e.g., a human cell, a monkey cell, a hamster cell, a rat cell, a mouse cell, or an insect cell) or a hybridoma.
- host cells examples include the COS-7 line of monkey kidney cells (ATCC CRL 1651) (see Gluzman et al., 1981 , Cell 23:175), L cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells or their derivatives such as Veggie CHO and related cell lines which grow in serum-free media (see Rasmussen et al., 1998 , Cytotechnology 28:31) or CHO strain DX-B11, which is deficient in DHFR (see Urlaub et al., 1980 , Proc. Natl. Acad. Sci.
- COS-7 line of monkey kidney cells ATCC CRL 1651
- L cells C127 cells
- 3T3 cells ATCC CCL 163
- CHO Chinese hamster ovary
- a host cell is a mammalian host cell, but is not a human host cell.
- a host cell is a cultured cell that can be transformed or transfected with a polypeptide-encoding nucleic acid, which can then be expressed in the host cell.
- the phrase “recombinant host cell” can be used to denote a host cell that has been transformed or transfected with a nucleic acid to be expressed.
- a host cell also can be a cell that comprises the nucleic acid but does not express it at a desired level unless a regulatory sequence is introduced into the host cell such that it becomes operably linked with the nucleic acid. It is understood that the term host cell refers not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to, e.g., mutation or environmental influence, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.
- recombinant antibody refers to an antibody that is expressed from a cell (or cell line) transfected with an expression vector (or possibly more than one expression vector) comprising the coding sequence of the antibody, or a portion thereof (e.g., a DNA sequence encoding a heavy chain or a light chain variable region as described herein).
- said coding sequence is not naturally associated with the cell.
- a recombinant antibody has a glycosylation pattern that is different than the glycosylation pattern of an antibody having the same sequence if it were to exist in nature.
- a recombinant antibody is expressed in a mammalian host cell which is not a human host cell. Notably, individual mammalian host cells have unique glycosylation patterns.
- an antibody refers to that amount of an antibody, or an antigen binding portion thereof that binds OX40, which is sufficient to effect treatment of a disease associated with OX40 signaling, as described herein, when administered to a subject.
- Therapeutically effective amounts of antibodies provided herein, when used alone or in combination, will vary depending upon the relative activity of the antibodies and combinations (e.g., in inhibiting cell growth) and depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- isolated refers to a protein (e.g., an antibody) that is substantially free of other cellular material.
- an isolated antibody is substantially free of other proteins from the same species.
- an isolated antibody is expressed by a cell from a different species and is substantially free of other proteins from the different species.
- a protein may be rendered substantially free of naturally associated components (or components associated with the cellular expression system used to produce the antibody) by isolation, using protein purification techniques well known in the art.
- the antibodies, or antigen binding fragments, of the invention are isolated.
- OX40 activation refers to activation of the OX40 receptor. Generally, OX40 activation results in signal transduction.
- OX40 refers to any native OX40 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
- the term encompasses “full-length,” unprocessed OX40 as well as any form of OX40 that results from processing in the cell.
- the term also encompasses naturally occurring variants of OX40, for example, splice variants or allelic variants.
- the amino acid sequence of an exemplary human OX40 lacking the signal peptide is shown in SEQ ID NO.
- the antibody, or fragment, of the invention binds to OX40 as set forth in SEQ ID NO: 217.
- the present invention pertains to OX40 binding proteins, particularly anti-OX40 antibodies, or antigen-binding portions thereof, and uses thereof.
- Various aspects of the invention relate to antibodies and antibody fragments, pharmaceutical compositions, nucleic acids, recombinant expression vectors, and host cells for making such antibodies and fragments.
- Methods of using the antibodies of the invention to detect human OX40, to stimulate OX40 activity, either in vitro or in vivo, and to prevent or treat disorders such as cancer are also encompassed by the invention.
- novel human antibody heavy and light chain variable regions and CDRs that are specific to human OX40.
- the invention provides an anti-OX40 antibody, or an antigen-binding fragment thereof, that comprises a heavy chain having a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201.
- the invention provides an anti-OX40 antibody, or an antigen-binding fragment thereof, that comprises a light chain having a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO.
- the invention provides an anti-OX40 antibody, or an antigen-binding fragment thereof, that comprises a light chain having a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO.
- SEQ ID NO. 20 SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213; and a heavy chain having a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO.
- SEQ ID NO. 7 SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201.
- the present disclosure provides a human antibody of an IgG class that binds to a human OX40 epitope with a binding affinity of at least 10 ⁇ 6 M, where the antibody, or antigen-binding fragment, has a heavy chain variable domain sequence which is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, or identical, to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO.
- SEQ ID NO. 34 SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201, and has a light chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, or identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO.
- SEQ ID NO. 25 SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the invention features an isolated anti-hOX40 human antibody comprising a heavy chain/light chain variable domain amino acid sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called OX1A11 herein), SEQ ID NO. 3/SEQ ID NO. 4 (called OX1B1 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called OX1B2 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called OX1B3 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called OX1C4 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called OX1C5 herein), SEQ ID NO. 13/SEQ ID NO.
- SEQ ID NO. 14 (called OX1D9 herein), SEQ ID NO. 15/SEQ ID NO. 16 (called OX1E10 herein), SEQ ID NO. 7/SEQ ID NO. 17 (called OX1E7 herein), SEQ ID NO. 3/SEQ ID NO. 18 (called OX1F2 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called OX1G9), SEQ ID NO. 21/SEQ ID NO. 22 (called OX2B12 herein), SEQ ID NO. 7/SEQ ID NO. 23 (called OX2B3 herein), SEQ ID NO. 24/SEQ ID NO. 25 (called OX2B4 herein), SEQ ID NO. 7/SEQ ID NO.
- Complementarity determining regions are known as hypervariable regions both in the light chain and the heavy chain variable domains of an antibody. The more highly conserved portions of variable domains are called the framework (FR).
- Complementarity determining regions (CDRs) and framework regions (FR) of a given antibody may be identified using systems known in the art, such as those described by Kabat et al. supra; Lefranc et al., supra and/or Honegger and Pluckthun, supra.
- the numbering system described in Kabat et al. (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.) is well known to those in the art.
- Kabat et al. defined a numbering system for variable domain sequences that is applicable to any antibody.
- Kabat et al. defined a numbering system for variable domain sequences that is applicable to any antibody.
- the present invention provides an anti-OX40 antibody comprising the CDRs of the heavy and light chain variable domains described in Table 1 (SEQ ID Nos: 1 to 212).
- the invention provides an anti-OX40 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region having the CDRs described in an amino acid sequence as set forth in any one of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO.
- the invention provides an anti-OX40 antibody, or antigen-binding fragment thereof, comprising a light chain variable region having the CDRs described in an amino acid sequence as set forth in any one of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO.
- the invention provides an anti-OX40 antibody, or antigen-binding fragment thereof, comprising a light chain variable region having the CDRs described in an amino acid sequence as set forth in any one of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
- SEQ ID NO. 10 SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO.
- SEQ ID NO. 1 SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201.
- the present invention features an isolated human anti-human OX40 (hOX40) antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable domain comprising a heavy chain CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID Nos: 49, 50 and 51; SEQ ID Nos: 55, 56 and 57; SEQ ID Nos: 61, 62 and 63; SEQ ID Nos: 67, 68, and 69; SEQ ID Nos: 73, 74, and 75; SEQ ID Nos: 79, 80, and 81; SEQ ID Nos: 85, 86, and 87; SEQ ID Nos: 91, 92, and 93; SEQ ID Nos: 103, 104 and 105; SEQ ID Nos: 109, 110 and 111; SEQ ID Nos: 118, 119 and 120; SEQ ID Nos: 133, 134 and 135; SEQ ID Nos: 139, 140
- a light chain variable domain comprising a light chain CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID Nos: 52, 53 and 54; SEQ ID Nos: 58, 59 and 60; SEQ ID Nos: 64, 65 and 66; SEQ ID Nos: 70, 71 and 72; SEQ ID Nos: 76, 77 and 78; SEQ ID Nos: 82, 83 and 84; SEQ ID Nos: 88, 89 and 90; SEQ ID Nos: 94, 95 and 96; SEQ ID Nos: 97, 98 and 99; SEQ ID Nos: 100, 101 and 102; SEQ ID Nos: 106, 107 and 108; SEQ ID Nos: 112, 113 and 114; SEQ ID Nos: 115, 116 and 117; SEQ ID Nos: 121, 122 and 123;
- the antibody of the invention comprises a heavy chain CDR set/light chain CDR set selected from the group consisting of the heavy chain variable domain CDR set of SEQ ID Nos: 49, 50 and 51/the light chain variable domain CDR set of 52, 53 and 54; the heavy chain variable domain CDR set of SEQ ID Nos: 55, 56 and 57/the light chain variable domain CDR set of 58, 59 and 60; the heavy chain variable domain CDR set of SEQ ID Nos: 61, 62, and 63/the light chain variable domain CDR set of 64, 65 and 66; the heavy chain variable domain CDR set of SEQ ID Nos: 67, 68 and 69/the light chain variable domain CDR set of 70, 71 and 72; the heavy chain variable domain CDR set of SEQ ID Nos: 73, 74 and 75/the light chain variable domain CDR set of 76, 77 and 78; the heavy chain variable domain CDR set of SEQ ID Nos: 79, 80 and 81/the light chain variable domain
- the invention provides an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a heavy chain comprising a CDR3 domain as set forth in any one of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- variable domain comprising an amino acid sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% identity to a sequence as set forth in any one of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- the invention provides an anti-OX40 antibody, or an antigen-binding fragment thereof, comprising a light chain comprising a CDR3 domain as set forth in any one of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO.
- SEQ ID NO. 40 SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213, and having a light chain variable domain comprising an amino acid sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% identity to a sequence as set forth in any one of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO.
- SEQ ID NO. 20 SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the CDR3 domain is held constant, while variability may be introduced into the remaining CDRs and/or framework regions of the heavy and/or light chains, while the antibody, or antigen binding fragment thereof, retains the ability to bind to OX40 and retains the functional characteristics, e.g., binding affinity and/or the ability to activate T cells, of the parent.
- One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an antigen binding protein.
- An antigen binding protein may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently.
- the CDRs permit the antigen binding protein to specifically bind to a particular antigen of interest.
- the substitutions made within a heavy or light chain that is at least 95% identical are conservative amino acid substitutions.
- a “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity).
- R group side chain
- a conservative amino acid substitution will not substantially change the functional properties of a protein.
- the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art.
- Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having the antigen binding regions of any of the antibodies described in Table 1.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX1A11.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 1, and a light chain variable domain sequence as set forth in SEQ ID NO: 2.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 1, and a light chain variable domain comprising the CDRs of SEQ ID NO: 2.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 1, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 2.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 49; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 52.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX2E5.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 201, and a light chain variable domain sequence as set forth in SEQ ID NO: 202.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 201, and a light chain variable domain comprising the CDRs of SEQ ID NO: 202.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 201, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 202.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 205, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 204, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 203; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 208, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 207, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 206.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX2B12.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 21, and a light chain variable domain sequence as set forth in SEQ ID NO: 22.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 21, and a light chain variable domain comprising the CDRs of SEQ ID NO: 22.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 21, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 22.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 111, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 110, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 109; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 114, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 113, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 112.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX1B1.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 3, and a light chain variable domain sequence as set forth in SEQ ID NO: 4.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 3, and a light chain variable domain comprising the CDRs of SEQ ID NO: 4.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 3, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 4.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 57, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 56, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 55; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 60, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 59, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 58.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX5C1.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 46, and a light chain variable domain sequence as set forth in SEQ ID NO: 47.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 46, and a light chain variable domain comprising the CDRs of SEQ ID NO: 47.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 46, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 47.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 186, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 185, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 184; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 189, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 188, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 187.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX4D7.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 37, and a light chain variable domain sequence as set forth in SEQ ID NO: 38.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 37, and a light chain variable domain comprising the CDRs of SEQ ID NO: 38.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 37, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 38.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 159, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 158, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 157; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 162, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 161, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 160.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX5B9.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 44, and a light chain variable domain sequence as set forth in SEQ ID NO: 45.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 44, and a light chain variable domain comprising the CDRs of SEQ ID NO: 45.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 44, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 45.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 180, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 179, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 178; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 183, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 182, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 181.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX1C4.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 9, and a light chain variable domain sequence as set forth in SEQ ID NO: 10.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 9, and a light chain variable domain comprising the CDRs of SEQ ID NO: 10.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 9, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 10.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 75, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 74, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 73; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 77, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 76.
- the antibody may further be an IgG1 or an IgG4 isotype.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX4B5.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 193, and a light chain variable domain sequence as set forth in SEQ ID NO: 194.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 193, and a light chain variable domain comprising the CDRs of SEQ ID NO: 194.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 193, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 194.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 197, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 195, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 195; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 200, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 199, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 198.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX2B5.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 5, and a light chain variable domain sequence as set forth in SEQ ID NO: 209.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 5, and a light chain variable domain comprising the CDRs of SEQ ID NO: 209.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 5, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 209.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 61; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 212, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 211, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 210.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX2B4.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 24, and a light chain variable domain sequence as set forth in SEQ ID NO: 25.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 24, and a light chain variable domain comprising the CDRs of SEQ ID NO: 25.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 24, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 25.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 120, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 119, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 118; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 123, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 122, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 121.
- the present invention is directed to an antibody, or an antigen binding fragment thereof, having antigen binding regions of antibody OX2B3.
- the invention provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable domain sequence as set forth in SEQ ID NO: 7, and a light chain variable domain sequence as set forth in SEQ ID NO: 23.
- the invention is directed to an antibody having a heavy chain variable domain comprising the CDRs of SEQ ID NO: 7, and a light chain variable domain comprising the CDRs of SEQ ID NO: 23.
- the invention features an isolated human antibody, or antigen-binding fragment thereof, that comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 7, and comprises a light chain variable region having an amino acid sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to the sequence set forth in SEQ ID NO: 23.
- the invention features an anti-OX40 antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 69, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 68, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 67; and comprising a light chain variable region comprising a CDR3 domain comprising the amino acid as set forth in SEQ ID NO: 117, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO: 116, and a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 115.
- the antibody of the invention may further be an IgG1 or an IgG4 isotype.
- antibodies OX1B3, OX1E7, OX2B3, OX2B6, OX2F2, OX2G2, OX4D4, OX4G9, OX5D7 and OX5C11 have a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO. 7.
- antibodies OX1B1, OX1F2 and OX4A12 have a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO. 3.
- Antigen-binding fragments of antigen binding proteins of the invention may be produced by conventional techniques. Examples of such fragments include, but are not limited to, Fab and F(ab′)2 fragments.
- Single chain antibodies may be formed by linking heavy and light chain variable domain (Fv region) fragments via an amino acid bridge (short peptide linker), resulting in a single polypeptide chain.
- Fv region heavy and light chain variable domain
- short peptide linker short peptide linker
- Such single-chain Fvs have been prepared by fusing DNA encoding a peptide linker between DNAs encoding the two variable domain polypeptides (VL and VH).
- the resulting polypeptides can fold back on themselves to form antigen-binding monomers, or they can form multimers (e.g., dimers, trimers, or tetramers), depending on the length of a flexible linker between the two variable domains (Kortt et al., 1997, Prot. Eng.
- the present disclosure provides a Fab fragment, having a variable domain region from a heavy chain and a variable domain region from a light chain, wherein the heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99%, or 100% identical, to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO.
- SEQ ID NO. 42 SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201, and that has a light chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99%, or 100% identical to the amino acid sequence consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO.
- the human antibody Fab fragment has both a heavy chain variable domain region and a light chain variable domain region wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO.
- the present disclosure provides a single chain human antibody, having a variable domain region from a heavy chain and a variable domain region from a light chain and a peptide linker connection the heavy chain and light chain variable domain regions, wherein the heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO.
- SEQ ID NO. 34 SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201, and that has a light chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99%, or 100% identical to the amino acid sequence consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO.
- SEQ ID NO. 25 SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the human single chain antibody has both a heavy chain variable domain region and a light chain variable domain region, wherein the single chain human antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 7/SEQ ID NO. 17, SEQ ID NO. 3/SEQ ID NO. 18, SEQ ID NO.
- SEQ ID NO. 20 SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 7/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 25, SEQ ID NO. 7/SEQ ID NO. 26, SEQ ID NO. 7/SEQ ID NO. 27, SEQ ID NO. 7/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 3/SEQ ID NO. 33, SEQ ID NO. 34/SEQ ID NO. 35, SEQ ID NO. 7/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO.
- IgG antibodies may be derived from an IgM antibody, for example, and vice versa.
- Such techniques allow the preparation of new antibodies that possess the antigen-binding properties of a given antibody (the parent antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody.
- Recombinant DNA techniques may be employed. Cloned DNA encoding particular antibody polypeptides may be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype (Lantto et al., 2002, Methods Mol. Biol. 178:303-16).
- the antibody of the invention is a human IgG1 antibody.
- the antibody of the invention is a human IgG4 antibody.
- the present disclosure provides a number of antibodies structurally characterized by the amino acid sequences of their variable domain regions.
- the amino acid sequences can undergo some changes while retaining their high degree of binding to their specific targets. More specifically, many amino acids in the variable domain region can be changed with conservative substitutions and it is predictable that the binding characteristics of the resulting antibody will not differ from the binding characteristics of the wild type antibody sequence.
- an antibody, or antigen-binding fragment thereof, of the invention has a dissociation constant (K D ) of 1 ⁇ 10 ⁇ 6 M or less; 5 ⁇ 10 ⁇ 7 M or less; 1 ⁇ 10 ⁇ 7 M or less; 5 ⁇ 10 ⁇ 8 M or less; 1 ⁇ 10 ⁇ 8 M or less; 5 ⁇ 10 ⁇ 9 M or less; or 1 ⁇ 10 ⁇ 9 M or less.
- K D dissociation constant
- the antibody, or antigen-binding fragment thereof, of the invention as a K D from 1 ⁇ 10 ⁇ 7 M to 1 ⁇ 10 ⁇ 10 M.
- the antibody, or antigen-binding fragment thereof, of the invention as a K D from 1 ⁇ 10 ⁇ 8 M to 1 ⁇ 10 ⁇ 10 M.
- K D is measured by a radiolabeled antigen binding assay (RIA).
- RIA radiolabeled antigen binding assay
- an RIA is performed with the Fab version of an antibody of interest and its antigen.
- solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of ( 125 I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)).
- K D is measured using a BIACORE surface plasmon resonance assay.
- surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE system (Biacore Life Sciences division of GE Healthcare, Piscataway, N.J.). Surface plasmon resonance can also be used to determine K off and K a values.
- antigen binding proteins of the present invention have a binding affinity (K a ) for OX40 of at least 10 3 M ⁇ 1 S ⁇ 1 .
- the antigen binding proteins exhibit a K a of at least 10 3 M ⁇ 1 S ⁇ 1 , at least 10 4 M ⁇ 1 S ⁇ 1 , at least 10 5 M ⁇ 1 S ⁇ 1 , or at least 10 6 M ⁇ 1 S ⁇ 1 .
- the antigen binding proteins exhibit a K a of at least 10 7 M ⁇ 1 S ⁇ 1 .
- the antigen binding proteins exhibit a K a of at least 10 7 M ⁇ 1 S ⁇ 1 or at least 10 8 M ⁇ 1 S ⁇ 1 .
- the anti-OX40 antibody, or fragment thereof, of the invention has a K a of at least 10 3 -10 7 M ⁇ 1 S ⁇ 1 .
- the antigen binding protein exhibits a K a substantially the same as that of an antibody described herein in the Examples. K a can be determined by Biacore testing, for example with Biacore 3000 or T200.
- the present disclosure provides an antigen binding protein that has a low dissociation rate from OX40.
- the antigen binding protein has a K off of 1 ⁇ 10 ⁇ 4 to 10 ⁇ 1 sec ⁇ 1 or lower.
- the K off is 5 ⁇ 10 ⁇ 5 to 10 ⁇ 1 sec ⁇ 1 or lower.
- the K off is 5 ⁇ 10 ⁇ 6 to 10 ⁇ 1 sec ⁇ 1 or lower.
- the K off is substantially the same as an antibody described herein.
- the antigen binding protein binds to OX40 with substantially the same K off as an antibody described herein.
- the present disclosure provides an antigen binding protein that inhibits an activity of OX40.
- the antigen binding protein has an IC 50 of 1000 nM or lower. In another embodiment, the IC 50 is 100 nM or lower; in another embodiment, the IC 50 is 10 nM or lower. In another embodiment, the IC 50 is substantially the same as that of an antibody described herein in the Examples. In another embodiment, the antigen binding protein inhibits an activity of OX40 with substantially the same IC 50 as an antibody described herein.
- the present disclosure provides an antigen binding protein that binds to OX40 expressed on the surface of a cell and, when so bound, inhibits OX40 signaling activity in the cell without causing a significant reduction in the amount of OX40 on the surface of the cell. Any method for determining or estimating the amount of OX40 on the surface and/or in the interior of the cell can be used. In other embodiments, binding of the antigen binding protein to the OX40-expressing cell causes less than about 75%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, 1%, or 0.1% of the cell-surface OX40 to be internalized.
- the present disclosure provides an antigen binding protein having a half-life of at least one day in vitro or in vivo (e.g., when administered to a human subject).
- the antigen binding protein has a half-life of at least three days.
- the antigen binding protein has a half-life of four days or longer.
- the antigen binding protein has a half-life of eight days or longer.
- the antigen binding protein is derivatized or modified such that it has a longer half-life as compared to the underivatized or unmodified antigen binding protein.
- the antigen binding protein contains one or more point mutations to increase serum half life, such as described in WO00/09560, incorporated by reference herein.
- bispecific antigen binding protein e.g., antigen binding protein that bind to two different epitopes of OX40, or to an epitope of OX40 and an epitope of another molecule, via two different antigen binding sites or regions.
- bispecific antigen binding protein as disclosed herein can comprise a OX40 binding site from one of the herein-described antibodies and a second OX40 binding region from another of the herein-described antibodies, including those described herein by reference to other publications.
- a bispecific antigen binding protein may comprise an antigen binding site from one of the herein described antibodies and a second antigen binding site from another OX40 antibody that is known in the art, or from an antibody that is prepared by known methods or the methods described herein.
- bispecific antibodies Numerous methods of preparing bispecific antibodies are known in the art. Such methods include the use of hybrid-hybridomas as described by Milstein et al., 1983, Nature 305:537, and chemical coupling of antibody fragments (Brennan et al., 1985, Science 229:81; Glennie et al., 1987, J. Immunol. 139:2367; U.S. Pat. No. 6,010,902). Moreover, bispecific antibodies can be produced via recombinant means, for example by using leucine zipper moieties (i.e., from the Fos and Jun proteins, which preferentially form heterodimers; Kostelny et al., 1992, J. Immunol. 148:1547) or other lock and key interactive domain structures as described in U.S. Pat. No. 5,582,996. Additional useful techniques include those described in U.S. Pat. Nos. 5,959,083; and 5,807,706.
- the antigen binding protein comprises a derivative of an antibody.
- the derivatized antibody can comprise any molecule or substance that imparts a desired property to the antibody, such as increased half-life in a particular use.
- the derivatized antibody can comprise, for example, a detectable (or labeling) moiety (e.g., a radioactive, colorimetric, antigenic or enzymatic molecule, a detectable bead (such as a magnetic or electrodense (e.g., gold) bead), or a molecule that binds to another molecule (e.g., biotin or streptavidin), a therapeutic or diagnostic moiety (e.g., a radioactive, cytotoxic, or pharmaceutically active moiety), or a molecule that increases the suitability of the antibody for a particular use (e.g., administration to a subject, such as a human subject, or other in vivo or in vitro uses).
- a detectable (or labeling) moiety e.g
- an antibody examples include albumin (e.g., human serum albumin) and polyethylene glycol (PEG).
- Albumin-linked and PEGylated derivatives of antibodies can be prepared using techniques well known in the art.
- the antibody is conjugated or otherwise linked to transthyretin (TTR) or a TTR variant.
- TTR or TTR variant can be chemically modified with, for example, a chemical selected from the group consisting of dextran, poly(n-vinyl pyurrolidone), polyethylene glycols, propropylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols and polyvinyl alcohols.
- Oligomers that contain one or more antigen binding proteins may be employed as OX40 antagonists. Oligomers may be in the form of covalently-linked or non-covalently-linked dimers, trimers, or higher oligomers. Oligomers comprising two or more antigen binding protein are contemplated for use, with one example being a homodimer. Other oligomers include heterodimers, homotrimers, heterotrimers, homotetramers, heterotetramers, etc.
- One embodiment is directed to oligomers comprising multiple antigen binding proteins joined via covalent or non-covalent interactions between peptide moieties fused to the antigen binding proteins.
- Such peptides may be peptide linkers (spacers), or peptides that have the property of promoting oligomerization.
- Leucine zippers and certain polypeptides derived from antibodies are among the peptides that can promote oligomerization of antigen binding proteins attached thereto, as described in more detail below.
- the oligomers comprise from two to four antigen binding proteins.
- the antigen binding proteins of the oligomer may be in any form, such as any of the forms described above, e.g., variants or fragments.
- the oligomers comprise antigen binding proteins that have OX40 binding activity.
- an oligomer is prepared using polypeptides derived from immunoglobulins.
- Preparation of Fusion Proteins Comprising Certain Heterologous Polypeptides Fused to Various Portions of antibody-derived polypeptides (including the Fc domain) has been described, e.g., by Ashkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88:10535; Byrn et al., 1990, Nature 344:677; and Hollenbaugh et al., 1992 “Construction of Immunoglobulin Fusion Proteins”, in Current Protocols in Immunology, Suppl. 4, pages 10.19.1-10.19.11.
- Leucine zipper domains are peptides that promote oligomerization of the proteins in which they are found.
- Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., 1988, Science 240:1759), and have since been found in a variety of different proteins.
- the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize.
- leucine zipper domains suitable for producing soluble oligomeric proteins are described in WO 94/10308, and the leucine zipper derived from lung surfactant protein D (SPD) described in Hoppe et al., 1994, FEBS Letters 344:191.
- SPD lung surfactant protein D
- the use of a modified leucine zipper that allows for stable trimerization of a heterologous protein fused thereto is described in Fanslow et al., 1994, Semin. Immunol. 6:267-78.
- recombinant fusion proteins comprising an anti-OX40 antibody fragment or derivative fused to a leucine zipper peptide are expressed in suitable host cells, and the soluble oligomeric anti-OX40 antibody fragments or derivatives that form are recovered from the culture supernatant.
- Antigen binding proteins directed against OX40 can be used, for example, in assays to detect the presence of OX40 polypeptides, either in vitro or in vivo.
- the antigen binding proteins also may be employed in purifying OX40 proteins by immunoaffinity chromatography. Blocking antigen binding proteins can be used in the methods disclosed herein.
- Such antigen binding proteins that function as OX40 antagonists may be employed in treating any OX40-induced condition, including but not limited to various cancers.
- Antigen binding proteins may be employed in an in vitro procedure, or administered in vivo to inhibit OX40-induced biological activity. Disorders caused or exacerbated (directly or indirectly) by the proteolytic of OX40, examples of which are provided herein, thus may be treated.
- the present invention provides a therapeutic method comprising in vivo administration of a OX40 blocking antigen binding protein to a mammal in need thereof in an amount effective for reducing a OX40-induced biological activity.
- antigen binding proteins include human monoclonal antibodies that inhibit a biological activity of OX40.
- Antigen binding proteins may be prepared by any of a number of conventional techniques. For example, they may be purified from cells that naturally express them (e.g., an antibody can be purified from a hybridoma that produces it), or produced in recombinant expression systems, using any technique known in the art. See, for example, Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds.), Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Land (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1988).
- any expression system known in the art can be used to make the recombinant polypeptides, including antibodies and antibody fragments described herein, of the invention.
- host cells are transformed with a recombinant expression vector that comprises DNA encoding a desired polypeptide.
- the host cells that may be employed are prokaryotes, yeast or higher eukaryotic cells.
- Prokaryotes include gram negative or gram positive organisms, for example E. coli or bacilli.
- Higher eukaryotic cells include insect cells and established cell lines of mammalian origin.
- suitable mammalian host cell lines include the COS-7 line of monkey kidney cells (ATCC CRL 1651) (Gluzman et al., 1981, Cell 23:175), L cells, 293 cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells, HeLa cells, BHK (ATCC CRL 10) cell lines, and the CV1/EBNA cell line derived from the African green monkey kidney cell line CV1 (ATCC CCL 70) as described by McMahan et al., 1991, EMBO J. 10: 2821.
- Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are described by Pouwels et al. (Cloning Vectors: A Laboratory Manual, Elsevier, N.Y., 1985).
- the transformed cells can be cultured under conditions that promote expression of the polypeptide, and the polypeptide recovered by conventional protein purification procedures.
- One such purification procedure includes the use of affinity chromatography, e.g., over a matrix having all or a portion (e.g., the extracellular domain) of OX40 bound thereto.
- Polypeptides contemplated for use herein include substantially homogeneous recombinant mammalian anti-OX40 antibody polypeptides substantially free of contaminating endogenous materials.
- Antigen binding proteins may be prepared, and screened for desired properties, by any of a number of known techniques. Certain of the techniques involve isolating a nucleic acid encoding a polypeptide chain (or portion thereof) of an antigen binding protein of interest (e.g., an anti-OX40 antibody), and manipulating the nucleic acid through recombinant DNA technology.
- the nucleic acid may be fused to another nucleic acid of interest, or altered (e.g., by mutagenesis or other conventional techniques) to add, delete, or substitute one or more amino acid residues, for example.
- Antibodies and fragments thereof of the present disclosure can be produced using any standard methods known in the art.
- the polypeptides are produced by recombinant DNA methods by inserting a nucleic acid sequence (a cDNA) encoding the polypeptide into a recombinant expression vector and expressing the DNA sequence under conditions promoting expression.
- the invention includes nucleic acids encoding any of the polypeptide sequences described in SEQ ID Nos: 1 to 216, as well as vectors comprising said nucleic acid sequences.
- Nucleic acids encoding any of the various polypeptides disclosed herein may be synthesized chemically. Codon usage may be selected so as to improve expression in a cell. Such codon usage will depend on the cell type selected. Specialized codon usage patterns have been developed for E. coli and other bacteria, as well as mammalian cells, plant cells, yeast cells and insect cells.
- the DNA encoding the polypeptide is operably linked to suitable transcriptional or translational regulatory elements derived from mammalian, viral, or insect genes.
- suitable transcriptional or translational regulatory elements include a transcriptional promoter, an optional operator sequence to control transcription, a sequence encoding suitable mRNA ribosomal binding sites, and sequences that control the termination of transcription and translation.
- the ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants is additionally incorporated.
- the recombinant DNA can also include any type of protein tag sequence that may be useful for purifying the protein.
- protein tags include but are not limited to a histidine tag, a FLAG tag, a myc tag, an HA tag, or a GST tag.
- Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts can be found in Cloning Vectors: A Laboratory Manual, (Elsevier, N.Y., 1985).
- the expression construct is introduced into the host cell using a method appropriate to the host cell.
- a variety of methods for introducing nucleic acids into host cells are known in the art, including, but not limited to, electroporation; transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipofection; and infection (where the vector is an infectious agent).
- Suitable host cells include prokaryotes, yeast, mammalian cells, or bacterial cells.
- Suitable bacteria include gram negative or gram positive organisms, for example, E. coli or Bacillus spp. Yeast, preferably from the Saccharomyces species, such as S. cerevisiae , may also be used for production of polypeptides.
- Various mammalian or insect cell culture systems can also be employed to express recombinant proteins. Baculovirus systems for production of heterologous proteins in insect cells are reviewed by Luckow and Summers, (Bio/Technology, 6:47, 1988).
- suitable mammalian host cell lines include endothelial cells, COS-7 monkey kidney cells, CV-1, L cells, C127, 3T3, Chinese hamster ovary (CHO), human embryonic kidney cells, HeLa, 293, 293T, and BHK cell lines.
- Purified polypeptides are prepared by culturing suitable host/vector systems to express the recombinant proteins. For many applications, the small size of many of the polypeptides disclosed herein would make expression in E. coli as the preferred method for expression. The protein is then purified from culture media or cell extracts.
- Proteins can also be produced using cell-translation systems.
- the nucleic acids encoding the polypeptide must be modified to allow in vitro transcription to produce mRNA and to allow cell-free translation of the mRNA in the particular cell-free system being utilized (eukaryotic such as a mammalian or yeast cell-free translation system or prokaryotic such as a bacterial cell-free translation system.
- OX40-binding polypeptides can also be produced by chemical synthesis (such as by the methods described in Solid Phase Peptide Synthesis, 2nd ed., 1984, The Pierce Chemical Co., Rockford, Ill.). Modifications to the protein can also be produced by chemical synthesis.
- polypeptides of the present disclosure can be purified by isolation/purification methods for proteins generally known in the field of protein chemistry.
- Non-limiting examples include extraction, recrystallization, salting out (e.g., with ammonium sulfate or sodium sulfate), centrifugation, dialysis, ultrafiltration, adsorption chromatography, ion exchange chromatography, hydrophobic chromatography, normal phase chromatography, reversed-phase chromatography, gel filtration, gel permeation chromatography, affinity chromatography, electrophoresis, countercurrent distribution or any combinations of these.
- polypeptides may be exchanged into different buffers and/or concentrated by any of a variety of methods known to the art, including, but not limited to, filtration and dialysis.
- the purified polypeptide is preferably at least 85% pure, more preferably at least 95% pure, and most preferably at least 98% pure. Regardless of the exact numerical value of the purity, the polypeptide is sufficiently pure for use as a pharmaceutical product.
- the present disclosure provides monoclonal antibodies that bind to OX40.
- Monoclonal antibodies may be produced using any technique known in the art, e.g., by immortalizing spleen cells harvested from the transgenic animal after completion of the immunization schedule.
- the spleen cells can be immortalized using any technique known in the art, e.g., by fusing them with myeloma cells to produce hybridomas.
- Myeloma cells for use in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas).
- Examples of suitable cell lines for use in mouse fusions include Sp-20, P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 4 1, Sp210-Ag14, FO, NSO/U, MPC-11, MPC11-X45-GTG 1.7 and S194/5XXO Bul; examples of cell lines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F and 48210.
- Other cell lines useful for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2 and UC729-6.
- the binding polypeptides of the invention may further comprise post-translational modifications.
- post-translational protein modifications include phosphorylation, acetylation, methylation, ADP-ribosylation, ubiquitination, glycosylation, carbonylation, sumoylation, biotinylation or addition of a polypeptide side chain or of a hydrophobic group.
- the modified soluble polypeptides may contain non-amino acid elements, such as lipids, poly- or mono-saccharide, and phosphates.
- a preferred form of glycosylation is sialylation, which conjugates one or more sialic acid moieties to the polypeptide. Sialic acid moieties improve solubility and serum half-life while also reducing the possible immunogeneticity of the protein. See Raju et al. Biochemistry. 2001 31; 40(30):8868-76.
- modified forms of the subject soluble polypeptides comprise linking the subject soluble polypeptides to nonproteinaceous polymers.
- the polymer is polyethylene glycol (“PEG”), polypropylene glycol, or polyoxyalkylenes, in the manner as set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.
- PEG is a water soluble polymer that is commercially available or can be prepared by ring-opening polymerization of ethylene glycol according to methods well known in the art (Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3, pages 138-161).
- the term “PEG” is used broadly to encompass any polyethylene glycol molecule, without regard to size or to modification at an end of the PEG, and can be represented by the formula: X—O(CH 2 CH 2 O) n —CH 2 CH 2 OH (1), where n is 20 to 2300 and X is H or a terminal modification, e.g., a C 1-4 alkyl.
- the PEG of the invention terminates on one end with hydroxy or methoxy, i.e., X is H or CH 3 (“methoxy PEG”).
- a PEG can contain further chemical groups which are necessary for binding reactions; which results from the chemical synthesis of the molecule; or which is a spacer for optimal distance of parts of the molecule.
- such a PEG can consist of one or more PEG side-chains which are linked together. PEGs with more than one PEG chain are called multiarmed or branched PEGs. Branched PEGs can be prepared, for example, by the addition of polyethylene oxide to various polyols, including glycerol, pentaerythriol, and sorbitol.
- a four-armed branched PEG can be prepared from pentaerythriol and ethylene oxide.
- Branched PEG are described in, for example, EP-A 0 473 084 and U.S. Pat. No. 5,932,462.
- One form of PEGs includes two PEG side-chains (PEG2) linked via the primary amino groups of a lysine (Monfardini et al., Bioconjugate Chem. 6 (1995) 62-69).
- the serum clearance rate of PEG-modified polypeptide may be decreased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90%, relative to the clearance rate of the unmodified binding polypeptide.
- the PEG-modified polypeptide may have a half-life (t 1/2 ) which is enhanced relative to the half-life of the unmodified protein.
- the half-life of PEG-binding polypeptide may be enhanced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400% or 500%, or even by 1000% relative to the half-life of the unmodified binding polypeptide.
- the protein half-life is determined in vitro, such as in a buffered saline solution or in serum. In other embodiments, the protein half-life is an in vivo half-life, such as the half-life of the protein in the serum or other bodily fluid of an animal.
- anti-OX40 antibodies or antigen binding fragments disclosed herein may be used in such therapeutic methods. Examples of anti-OX40 antibodies and antigen binding fragments that may be used in the therapeutic methods and compositions of the invention are described above.
- the anti-OX40 antibodies and antibody fragments of the invention are used to treat a disease requiring either stimulation of immune responses or suppression.
- OX40 stimulation (with agonists) is useful in treating a disease where the immune response (preferentially T cells) needs to be boosted.
- OX40/OX40L blockade is useful in treating a disease in which inflammation needs to be reduced, for example during autoimmunity or allergy.
- OX40/OX40L blockade is usually done by using OX40L blocking antibodies.
- the disease is selected from the group consisting of cancers, autoimmune diseases and infections.
- anti-OX40 antibodies and antibody fragments of the invention may be used to treat cancer.
- anti-OX40 antibodies and antibody fragments of the invention may be used in treating infection (e.g., infection with a bacteria or virus or other pathogen).
- infection e.g., infection with a bacteria or virus or other pathogen.
- the infection is with a virus and/or a bacteria.
- the infection is with a pathogen.
- anti-OX40 antibodies and antibody fragments of the invention may be used to enhance immune function (e.g., by upregulating cell-mediated immune responses), e.g., in an individual having cancer.
- the present disclosure further provides a method for treating a broad spectrum of mammalian cancers, infectious diseases, or autoimmune reactions, comprising administering an anti-OX40 polypeptide using the antibodies, and antibody fragments, disclosed herein.
- the invention provides a method of treating cancer by administering an anti-human OX40 antibody to a subject in need thereof.
- antibodies, and fragments thereof, that may be used in the therapeutics methods disclosed herein include an anti-human OX40 human antibody of an IgG class having a binding affinity of at least 10 ⁇ 6 M, or an anti-human OX40 Fab antibody fragment comprising a heavy chain variable region and a light chain variable region from the antibody sequences described in SEQ ID Nos.
- the methods disclosed herein comprise administering an isolated human antibody comprising a heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, to an amino acid sequence selected from the group consisting of heavy chain and a variable domain region from a light chain, wherein the heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99%, or 100% identical, to the amino acid sequences selected from the group consisting of SEQ ID NO.
- SEQ ID NO. 3 SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201, and having a light chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, to an amino acid sequence selected from the group consisting of SEQ ID NO.
- SEQ ID NO. 4 SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO.
- the methods disclosed herein comprise administering an IgG human anti-hOX40 antibody comprising a heavy chain variable domain sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO.
- SEQ ID NO. 2 SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the methods described herein include the use of a Fab fragment comprising a heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO.
- SEQ ID NO. 193 and SEQ ID NO. 201 and comprising a light chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO.
- the methods described herein include the use of a human Fab antibody fragment comprising a heavy chain variable domain sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO.
- SEQ ID NO. 19 SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201, and comprising a light chain variable domain sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO.
- SEQ ID NO. 26 SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the methods described herein include the use of a single chain human antibody, e.g., scFv, comprising a heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO.
- a single chain human antibody e.g., scFv
- a heavy chain variable domain sequence that is at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical, to an amino acid sequence selected from
- SEQ ID NO. 2 SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO.
- the methods described herein include the use of a single chain human antibody comprising a heavy chain variable domain having an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO.
- SEQ ID NO. 11 SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 19, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 34, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 193 and SEQ ID NO. 201, and comprising a light chain variable domain having an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO.
- SEQ ID NO. 22 SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 194, SEQ ID NO. 202, SEQ ID NO. 209 and SEQ ID NO. 213.
- the isolated anti-OX40 human antibody used in the methods of the invention comprises a heavy chain and a light chain wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called OX1A11 herein), SEQ ID NO. 3/SEQ ID NO. 4 (called OX1B1 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called OX1B2 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called OX1B3 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called OX1C4 herein), SEQ ID NO. 11/SEQ ID NO.
- OX4B5 SEQ ID NO. 201/SEQ ID NO. 202
- OX2E5 SEQ ID NO. 5/SEQ ID NO. 209
- OX5C11 SEQ ID NO. 7/SEQ ID NO. 213
- a Fab fragment used in the methods of the invention has both a heavy chain variable domain region and a light chain variable domain region wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called OX1A11 herein), SEQ ID NO. 3/SEQ ID NO. 4 (called OX1B1 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called OX1B2 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called OX1B3 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called OX1C4 herein), SEQ ID NO. 11/SEQ ID NO.
- OX4B5 SEQ ID NO. 201/SEQ ID NO. 202
- OX2E5 SEQ ID NO. 5/SEQ ID NO. 209
- OX5C11 SEQ ID NO. 7/SEQ ID NO. 213
- a human single chain antibody has both a heavy chain variable domain region and a light chain variable domain region, wherein the single chain human antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 7/SEQ ID NO. 17, SEQ ID NO. 3/SEQ ID NO. 18, SEQ ID NO.
- SEQ ID NO. 20 SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 7/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 25, SEQ ID NO. 7/SEQ ID NO. 26, SEQ ID NO. 7/SEQ ID NO. 27, SEQ ID NO. 7/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 3/SEQ ID NO. 33, SEQ ID NO. 34/SEQ ID NO. 35, SEQ ID NO. 7/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO.
- Anti-OX40 antibodies and antibody fragments of the invention may be used to treat a subject having cancer, including, for example, a solid tumor or leukemic cell that expresses OX40 on the cell surface.
- the OX40 antibodies and antibody fragments described herein are useful in treating, delaying the progression of, preventing relapse of or alleviating a symptom of a cancer or other neoplastic condition in a subject in need thereof.
- a cancer that may be treated using the antibodies and fragments of the invention include, but are not limited to, prostate cancer, breast cancer, ovarian cancer, head and neck cancer, bladder cancer, melanoma, colorectal cancer, pancreatic cancer, lung cancer, leiomyoma, leiomyo sarcoma, glioma, glioblastoma, esophageal cancer, liver cancer, kidney cancer, stomach cancer, colon cancer, cervical cancer, uterine cancer, liver cancer and a hematological cancer.
- hematological cancer refers to a cancer of the blood, and includes leukemia, lymphoma and myeloma among others.
- Leukemia refers to a cancer of the blood in which too many white blood cells that are ineffective in fighting infection are made, thus crowding out the other parts that make up the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic.
- Lymphoma refers to a group of blood cancers that develop in the lymphatic system.
- Myeloma refers to a cancer that forms in a type of white blood cell called a plasma cell.
- leukemia that may be treated using the antibodies and fragments of the invention, include B chronic lymphocytic leukemia (B-CLL), B and T acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); hairy cell leukemia (HCL); Myeloproliferative disorder/neoplasm (MPDS); and myelodysplasia syndrome.
- B-CLL B chronic lymphocytic leukemia
- ALL acute myeloid leukemia
- CLL chronic lymphocytic leukemia
- CML chronic myelogenous leukemia
- HCL hairy cell leukemia
- MPDS Myeloproliferative disorder/neoplasm
- myelodysplasia syndrome myelodysplasia syndrome.
- NHL low grade/follicular non-Hodgkin's lymphoma
- SL small lymphocytic
- NHL intermediate grade/follicular NHL
- intermediate grade diffuse NHL high
- myeloma that may be treated using the antibodies and fragments of the invention include multiple myeloma (MM), plasma cell myeloma, plamocytoma, giant cell myeloma, heavy-chain myeloma, and light chain or Bence-Jones myeloma.
- MM multiple myeloma
- plasma cell myeloma plamocytoma
- giant cell myeloma giant cell myeloma
- heavy-chain myeloma heavy-chain myeloma
- light chain or Bence-Jones myeloma MM
- Blockade of OX40 by antibodies can enhance an immune response against cancerous cells in the patient.
- An anti-OX40 antibody or antibody fragment disclosed herein can be used alone to inhibit the growth of cancerous tumors.
- an anti-OX40 antibody or antibody fragment disclosed herein can be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies.
- the present disclosure provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-OX40 antibody, or antigen-binding fragment thereof.
- the antibody or antibody fragment is a human anti-OX40 antibody or antibody fragment (such as any of the human anti-OX40 antibodies described herein).
- preferred cancers whose growth may be inhibited include cancers typically responsive to immunotherapy.
- antibodies and antibody fragments to OX40 described herein can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
- an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
- tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
- an anti-OX40 antibody or antibody fragment disclosed herein may be combined with a vaccination protocol.
- Many experimental strategies for vaccination against tumors have been devised. In one of these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
- tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. Many of these antigens can be shown to be the targets of tumor specific T cells found in the host.
- An anti-OX40 antibody or antibody fragment disclosed herein can be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins.
- the tumor antigen can include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means).
- Tumor antigen can also be “neo-antigens” expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e., bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
- tumor vaccines can include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
- HPV Human Papilloma Viruses
- HBV Hepatitis Viruses
- KHSV Kaposi's Herpes Sarcoma Virus
- Another form of tumor specific antigen which can be used in conjunction with an anti-OX40 antibody or antibody fragment disclosed herein is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot & Srivastava (1995) Science 269:1585-1588; Tamura et al. (1997) Science 278:117-120).
- DC Dendritic cells
- DC's can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle et al. (1998) Nature Medicine 4: 328-332). DCs can also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization can be effectively combined with OX40 blockade to activate more potent anti-tumor responses.
- An anti-OX40 antibody or antibody fragment disclosed herein can also be combined with other cancer treatments.
- An anti-OX40 antibody or antibody fragment disclosed herein can be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr et al. (1998) Cancer Research 58: 5301-5304).
- An example of such a combination is an anti-OX40 antibody in combination with decarbazine for the treatment of melanoma.
- Another example of such a combination is an anti-OX40 antibody in combination with interleukin-2 (IL-2) for the treatment of melanoma.
- IL-2 interleukin-2
- OX40 blockade The scientific rationale behind the combined use of OX40 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
- Other combination therapies that may result in synergy with an anti-OX40 antibody or antibody fragment disclosed herein through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
- Angiogenesis inhibitors can also be combined with an anti-OX40 antibody or antibody fragment disclosed herein. Inhibition of angiogenesis often leads to tumor cell death which may feed tumor antigens into host antigen presentation pathways.
- Bispecific antibodies can be used to target two separate antigens.
- anti-Fc receptor/anti-tumor antigen e.g., Her-2/neu
- bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses.
- the T cell arm of these responses would be augmented by the use of an anti-OX40 antibody or antibody fragment disclosed herein.
- antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
- Bispecific antibodies can be used to target two separate tumor antigens.
- a variety of tumor targets may be considered, including, for example, Her2, cMet, EGFR and VEGFR expressing tumors.
- the invention provides a bispecific antibody comprising an anti-OX40 antibody (or antigen binding fragment) comprising a heavy and light chain variable region sequence as described herein or a heavy and light chain variable region comprising a set of CDR sequences as described herein and an anti-Her2, an anti-EGFR, an anti-VEGFR (see, for examples, antibodies described in U.S. Pat. No. 9,029,510, incorporated by reference herein), or an anti-cMet antibody (or antigen binding portion thereof).
- the invention includes a bispecific antibody specific to OX40 and EGFR, wherein the antibody comprises an anti-OX40 antibody or fragment as disclosed herein and an anti-EGFR antibody or fragment as described in International Publication No. WO 2013/173255 or International Publication No. WO 2014/066530, both of which are incorporated by reference in their entireties herein.
- the invention includes a bispecific antibody specific to OX40 and VEGFR, wherein the antibody comprises an anti-OX40 antibody or fragment as disclosed herein and an anti-VEGFR antibody or fragment as described in U.S. Pat. No. 9,029,510, incorporated by reference in its entirety herein.
- the invention includes a bispecific antibody specific to OX40 and cMet, wherein the antibody comprises an anti-OX40 antibody or fragment as disclosed herein and an anti-cMet antibody or fragment as described in International Publication No. WO 2016/094455, incorporated by reference in its entirety herein.
- Anti-OX40 antibodies or antibody fragments disclosed herein can also be used in combination with bispecific antibodies that target, for example, Fc ⁇ or Fc ⁇ receptor-expressing effectors cells to tumor cells (U.S. Pat. Nos. 5,922,845 and 5,837,243).
- Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF- ⁇ (Kehrl et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard & O'Garra (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne et al. (1996) Science 274: 1363-1365). Antibodies to each of these entities can be used in combination with anti-OX40 antibodies and antibody fragments described herein to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
- Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge et al. (1998) Nature 393: 474-478) and can be used in conjunction with OX40 antibodies (Ito et al. (2000) Immunobiology 201 (5) 527-40).
- Activating antibodies to T cell costimulatory molecules such as CTLA-4, OX-40, 4-1BB, and ICOS may also provide for increased levels of T cell activation.
- OX40 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
- the present disclosure further provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-OX40 antibody, or antigen-binding portion thereof, such that the subject is treated for the infectious disease.
- the antibody is a human anti-human OX40 antibody or antibody fragment (such as any of the human anti-OX40 antibodies described herein).
- anti-OX40 antibodies and antibody fragments of the invention may be used in treating infection (e.g., infection with a bacteria or virus or other pathogen).
- infection e.g., infection with a bacteria or virus or other pathogen.
- the infection is with a virus and/or a bacteria.
- the infection is with a pathogen.
- pathogenic viruses causing infections treatable by the disclosed antibodies include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
- herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
- adenovirus e.g., influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie
- pathogenic bacteria causing infections treatable by the disclosed antibodies include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and gonococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lymes disease bacteria.
- the anti-OX40 antibodies and antibody fragments of the invention can be administered alone or in combination with one or more additional therapies. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
- the anti-OX40 antibodies and antibody fragments of the invention may be administered in conjunction with a chemotherapy or chemotherapeutic agent. In some embodiments, the anti-OX40 antibodies and antibody fragments of the invention may be administered in conjunction with a radiation therapy or radiotherapeutic agent. In some embodiments, the anti-OX40 antibodies and antibody fragments of the invention may be administered in conjunction with a targeted therapy or targeted therapeutic agent. In some embodiments, the anti-OX40 antibodies and antibody fragments of the invention may be administered in conjunction with an immunotherapy or immunotherapeutic agent, for example a monoclonal antibody.
- one or more anti-OX40 antibodies and antibody fragments of the invention can be administered, together (simultaneously) or at different times (sequentially).
- anti-OX40 antibodies and antibody fragments of the invention can be administered with another type of compound(s) for treating cancer or for inhibiting angiogenesis.
- the disclosed human anti-OX40 antibodies can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent.
- the antibody can be linked to the agent (as an immuno-complex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation.
- Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
- anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
- Cisplatin is intravenously administered as a 100 mg/ml dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days.
- Co-administration of the anti-OX40 antibodies and antibody fragments of the invention, with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells.
- Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
- OX40 is not constitutively expressed on naive T cells, but is induced after engagement of the T cell receptor (TCR).
- TCR T cell receptor
- the ligand for OX40, OX40L is predominantly expressed on antigen presenting cells.
- OX40 is highly expressed by activated CD4+ T cells, activated CD8+ T cells, memory T cells, and regulatory T cells.
- OX40 signaling can provide costimulatory signals to CD4 and CD8 T cells, leading to enhanced cell proliferation, survival, effector function and migration. OX40 signaling also enhances memory T cell development and function.
- an anti-OX40 antibody or antibody fragment as described herein may be co-administered with one or more additional antibodies that are effective in stimulating immune responses to thereby further enhance, stimulate or upregulate immune responses in a subject.
- the invention provides a method for stimulating an immune response in a subject comprising administering to the subject an anti-OX40 antibody or antibody fragment and one or more additional immunostimulatory antibodies, such as an anti-PD-1 antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated in the subject, for example to inhibit tumor growth or to stimulate an anti-viral response.
- an immune checkpoint inhibitor includes a drug or agent, e.g., an antibody, that can activate T cells which are inactive in the absence of the drug or agent due, at least in part, to signaling from a cancer cell which can maintain the inactive state of the T cell.
- an anti-OX40 antibody or antigen binding antibody fragment of the invention is used in combination with an immune checkpoint inhibitor for the treatment of cancer.
- an anti-OX40 antibody, or antigen binding fragment, described herein is administered in combination with an antibody which is an immune checkpoint inhibitor, including, but not limited to, an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, an anti-programmed death 1 (PD-1) antibody, or an anti-programmed death-ligand 1 (PD-L1) antibody.
- CTLA-4 anti-cytotoxic T-lymphocyte antigen 4
- PD-1 anti-programmed death 1
- PD-L1 anti-programmed death-ligand 1
- an anti-OX40 antibody, or antigen binding fragment, described herein is administered in combination with trastuzumab (Herceptin).
- the subject is administered an anti-OX40 antibody or antibody fragment and an anti-PD-1 antibody.
- the subject is administered an anti-OX40 antibody or antibody fragment selected from 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5, and an anti-PD-1 antibody.
- the subject is administered an anti-OX40 antibody or antibody fragment and an anti-PD-L1 antibody.
- the subject is administered an anti-OX40 antibody or antibody fragment selected from 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5, and an anti-PD-L1 antibody.
- the subject is administered an anti-OX40 antibody or antibody fragment and an anti-CTLA-4 antibody.
- the subject is administered an anti-OX40 antibody or antibody fragment selected from 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5, and an anti-CTLA-4 antibody.
- the invention provides a method for treating a hyperproliferative disease (e.g., cancer), comprising administering a OX40 antibody and a CTLA-4 antibody to a subject.
- a hyperproliferative disease e.g., cancer
- the anti-OX40 antibody is administered at a subtherapeutic dose
- the anti-CTLA-4 antibody is administered at a subtherapeutic dose
- both are administered at a subtherapeutic dose.
- a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulatory agent comprising administering an anti-OX40 antibody and a subtherapeutic dose of anti-CTLA-4 antibody to a subject.
- an anti-OX40 antibody, or antigen binding fragment (e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5), described herein is administered in combination with an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, for example ipilimumab (YERVOY) or tremelimumab (CP-675,206; MedImmune).
- CTLA-4 anti-cytotoxic T-lymphocyte antigen 4
- Another combination comprises administering a OX40 antibody or antibody fragment (e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5) and a PD-1 or PD-L1 antibody to a subject.
- a OX40 antibody or antibody fragment e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5
- a PD-1 or PD-L1 antibody e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5
- PD-1 or PD-L1 antibody e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5
- PD-1 or PD-L1 antibody e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9
- PD-L1 antibody for example avelumab (MSB0010718C), atezolizumab (TECENTRIQ) or durvalumab (MEDI4736).
- PD-L1 antibody for example avelumab (MSB0010718C), atezolizumab (TECENTRIQ) or durvalumab (MEDI4736).
- the anti-OX40 antibody is administered at a subtherapeutic dose
- the anti-PD-1 or PD-L1 antibody is administered at a subtherapeutic dose
- both are administered at a subtherapeutic dose.
- an anti-OX40 antibody, or antigen binding fragment (e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5), described herein is administered in conjunction with a PARP inhibitor (e.g., Olaparanib, Rucaparib, Niraparib, Cediranib, BMN673, Veliparib), Trabectedin, nab-paclitaxel (albumen-bound paclitaxel, ABRAXANE), Trebananib, Pazopanib, Cediranib, Palbociclib, everolimus, fluoropyrimidine (e.g., FOLFOX, FOLFIRI), IFL, regorafenib, Reolysin, Alimta, Zykadia, Sutent, Torisel (temsirolimus), Inlyta (axitinib, Pfizer), Afinitor (everolimus, Novartis), Nexavar (s
- an anti-OX40 antibody, or antigen binding fragment (e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5), described herein is administered in conjunction with an agonist directed against an activating co-stimulatory molecule.
- an activating co-stimulatory molecule may include CD40, CD226, CD28, GITR, CD137, CD27, HVEM, or CD127.
- the agonist directed against an activating co-stimulatory molecule is an agonist antibody that binds to CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127.
- an anti-human OX40 agonist antibody may be administered in conjunction with an antagonist directed against an inhibitory co-stimulatory molecule.
- an inhibitory co-stimulatory molecule may include CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase.
- the antagonist directed against an inhibitory co-stimulatory molecule is an antagonist antibody that binds to CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3 (e.g., LAG-3-IgG fusion protein (IMP321)), B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase.
- LAG-3 e.g., LAG-3-IgG fusion protein (IMP321)
- B7-H3, B7-H4 IDO e.g., TIGIT, MICA/B, or arginase.
- an anti-OX40 antibody, or antigen binding fragment e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5, described herein is administered in conjunction with an antagonist directed against CD19.
- an anti-OX40 antibody, or antigen binding fragment e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5), described herein is administered in conjunction with MOR00208.
- an anti-OX40 antibody, or antigen binding fragment e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5), described herein is administered in conjunction with an antagonist directed against CD38.
- an anti-OX40 antibody, or antigen binding fragment (e.g. 1A11, 2E5, 2B12, 1B1, 5C1, 4D7, 5B9, 1C4, 4B5), described herein is administered in conjunction with an angiogenesis inhibitor (e.g. bevacizumab, sorafenib, sunitinib, pazopanib) and everolimus.
- angiogenesis inhibitor e.g. bevacizumab, sorafenib, sunitinib, pazopanib
- Cancers whose growth may be inhibited using the antibodies of the instant disclosure include cancers typically responsive to immunotherapy.
- Representative examples of cancers for treatment with the combination therapy of the instant disclosure include those cancers specifically listed above in the discussion of monotherapy with anti-OX40 antibodies.
- Suitable routes of administering the antibody compositions described herein are in vivo and in vitro are well known in the art and can be selected by those of ordinary skill.
- the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous). Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.
- therapeutic formulations will generally be distinguished from other formulations in that they are substantially pyrogen free, or at least contain no more than acceptable levels of pyrogen as determined by the appropriate regulatory agency (e.g., FDA).
- compositions comprising the antigen binding proteins of the present disclosure may be administered with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration may be parenteral (e.g., intravenous, subcutaneous), oral, or topical, as non-limiting examples.
- any gene therapy technique using nucleic acids encoding the polypeptides of the invention, may be employed, such as naked DNA delivery, recombinant genes and vectors, cell-based delivery, including ex vivo manipulation of patients' cells, and the like.
- an anti-OX40 antibody, or antigen binding portion thereof, of the invention can be incorporated into a pharmaceutical composition suitable for parenteral administration.
- the anti-OX40 antibody, or antigen binding portion thereof will be prepared as an injectable solution containing 0.1-250 mg/ml antibody.
- the injectable solution can be composed of either a liquid or lyophilized dosage form in a flint or amber vial, ampoule or pre-filled syringe.
- the buffer can be L-histidine (1-50 mM), optimally 5-10 mM, at pH 5.0 to 7.0 (optimally pH 6.0).
- Other suitable buffers include but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate.
- Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0-300 mM (optimally 150 mM for a liquid dosage form).
- Cryoprotectants can be included for a lyophilized dosage form, principally 0-10% sucrose (optimally 0.5-1.0%).
- Other suitable cryoprotectants include trehalose and lactose.
- Bulking agents can be included for a lyophilized dosage form, principally 1-10% mannitol (optimally 2-4%).
- Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1-50 mM L-methionine (optimally 5-10 mM).
- Other suitable bulking agents include glycine, arginine, can be included as 0-0.05% polysorbate-80 (optimally 0.005-0.01%).
- Additional surfactants include but are not limited to polysorbate 20 and BRIJ surfactants.
- compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
- liquid solutions e.g., injectable and infusible solutions
- dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
- the preferred form depends on the intended mode of administration and therapeutic application.
- Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
- the preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
- an anti-OX40 antibody, or antigen binding portion thereof, described herein is administered by intravenous infusion or injection.
- an anti-OX40 antibody, or antigen binding portion thereof is administered by intramuscular or subcutaneous injection.
- compositions typically must be sterile and stable under the conditions of manufacture and storage.
- the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
- Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prolonged absorption of injectable compositions can be brought about by including, in the composition, an agent that delays absorption, for example, monostearate salts and gelatin.
- the anti-OX40 antibody, or antigen binding portion thereof, of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is subcutaneous injection, intravenous injection, or infusion. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
- the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- a carrier such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
- a therapeutically effective dose refers to a dose that produces the therapeutic effects for which it is administered.
- the exact dose will depend on the disorder to be treated, and may be ascertained by one skilled in the art using known techniques.
- the polypeptide is administered at about 0.01 ⁇ g/kg to about 50 mg/kg per day, preferably 0.01 mg/kg to about 30 mg/kg per day, most preferably 0.1 mg/kg to about 20 mg/kg per day.
- the polypeptide may be given daily (e.g., once, twice, three times, or four times daily) or preferably less frequently (e.g., weekly, every two weeks, every three weeks, monthly, or quarterly).
- adjustments for age as well as the body weight, general health, sex, diet, time of administration, drug interaction, and the severity of the disease may be necessary.
- the disclosed antibodies are administered by inhalation, but aerosolization of full IgG antibodies may prove limiting due to their molecular size ( ⁇ 150 kDa). To maximize available commercial aerosolization devices, smaller Fab fragments may be required.
- the subject anti-OX40 antibodies or antibody fragments of the invention can be used alone.
- any of the anti-OX40 antibodies provided herein is useful for detecting the presence of OX40 in a biological sample.
- a biological sample comprises a cell or tissue, such as a sample of a tumor (e.g., NSCLC or breast tumor).
- an anti-OX40 antibody for use in a method of diagnosis or detection is provided.
- a method of detecting the presence of OX40 in a biological sample is provided.
- the method comprises contacting the biological sample with an anti-OX40 antibody as described herein under conditions permissive for binding of the anti-OX40 antibody to OX40, and detecting whether a complex is formed between the anti-OX40 antibody and OX40.
- Such method may be an in vitro or in vivo method.
- an anti-OX40 antibody is used to select subjects eligible for therapy with an anti-OX40 antibody, e.g. where OX40 is a biomarker for selection of patients.
- Exemplary disorders that may be diagnosed using an antibody of the invention include cancer.
- the binding polypeptides of fragments thereof can be labeled or unlabeled for diagnostic purposes.
- diagnostic assays entail detecting the formation of a complex resulting from the binding of a binding polypeptide to OX40.
- the binding polypeptides or fragments can be directly labeled, similar to antibodies.
- labels can be employed, including, but not limited to, radionuclides, fluorescers, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors and ligands (e.g., biotin, haptens). Numerous appropriate immunoassays are known to the skilled artisan (see, for example, U.S. Pat. Nos.
- the binding polypeptides can be used in assays, such as agglutination assays. Unlabeled binding polypeptides can also be used in combination with another (one or more) suitable reagent which can be used to detect the binding polypeptide, such as a labeled antibody reactive with the binding polypeptide or other suitable reagent (e.g., labeled protein A).
- a suitable reagent which can be used to detect the binding polypeptide, such as a labeled antibody reactive with the binding polypeptide or other suitable reagent (e.g., labeled protein A).
- the binding polypeptides of the present disclosure can be utilized in enzyme immunoassays, wherein the subject polypeptides are conjugated to an enzyme.
- a biological sample comprising an OX40 protein is combined with the subject binding polypeptides, binding occurs between the binding polypeptides and the OX40 protein.
- a sample containing cells expressing an OX40 protein e.g., endothelial cells
- binding occurs between the binding polypeptides and cells bearing an OX40 protein recognized by the binding polypeptide.
- binding polypeptide-enzyme conjugate specifically bound to the cells can be determined, for example, by contacting the sample with a substrate of the enzyme which produces a color or other detectable change when acted on by the enzyme.
- the subject binding polypeptides can be unlabeled, and a second, labeled polypeptide (e.g., an antibody) can be added which recognizes the subject binding polypeptide.
- kits for use in detecting the presence of an OX40 protein in a biological sample using the antibodies or fragments thereof of the invention can also be prepared.
- kits will include an OX40 binding polypeptide, e.g., antibodies or fragments thereof, which binds to an OX40 protein or portion of said receptor, as well as one or more ancillary reagents suitable for detecting the presence of a complex between the binding polypeptide and the receptor protein or portions thereof.
- the polypeptide compositions of the present invention can be provided in lyophilized form, either alone or in combination with additional antibodies specific for other epitopes.
- the binding polypeptides and/or antibodies which can be labeled or unlabeled, can be included in the kits with adjunct ingredients (e.g., buffers, such as Tris, phosphate and carbonate, stabilizers, excipients, biocides and/or inert proteins, e.g., bovine serum albumin).
- adjunct ingredients e.g., buffers, such as Tris, phosphate and carbonate, stabilizers, excipients, biocides and/or inert proteins, e.g., bovine serum albumin.
- the binding polypeptides and/or antibodies can be provided as a lyophilized mixture with the adjunct ingredients, or the adjunct ingredients can be separately provided for combination by the user.
- these adjunct materials will be present in less than about 5% weight based on the amount of active binding polypeptide or antibody, and usually will be present in a total amount of at least about 0.001% weight based on polypeptide or antibody concentration.
- a second antibody capable of binding to the binding polypeptide can be provided in the kit, for instance in a separate vial or container.
- the second antibody if present, is typically labeled, and can be formulated in an analogous manner with the antibody formulations described above.
- FIG. 1 shows the binding of anti-OX40 antibody clones on activated human T-cells measured by the percent CD3+OX40+ T cells. The anti-OX40 clones that were tested are shown on the x-axis. FIG. 1 shows that most of the tested anti-OX40 clones are bound on T cells.
- OX40 + HEK293-NFkB-luciferase reporter stable cells were counted and re-suspended in RPMI-1640+5% FCS (complete medium). 6.7 ⁇ 10 4 cells/well (in 60 ⁇ l) were distributed in a white flat-bottom 96-well microplate. The cells were seeded in triplicate. Cells were stimulated by adding 60 ⁇ l of one of the following reagents: (1) Soluble TNF ⁇ (Biolegend; Ref. 570102; Lot. B204173) as a positive control; (2) Soluble anti-Histidine (Biolegend; Ref.
- FIG. 2A shows the luciferase activity measured by RLUs for the control experimental conditions after 6 hours of stimulation.
- unstimulated cells isotype control FeH3 antibody (Ctrl FeH3) and polyclonal anti-OX40 antibody did not show an increase in RLUs, indicating that the NFkB pathway was not activated.
- the positive controls soluble anti-Histidine+purified rhOX40L (rhOX40L+ ⁇ His) and soluble TNF ⁇ , showed higher RLUs, indicating an increase in NFkB activity, as expected.
- FIG. 2B shows luciferase activity measured by RLUs for the anti-OX40 antibody clones tested after 6 hours of stimulation.
- the luciferase activity was reveal by adding 100 ⁇ l/well of BIOGLO Luciferase Assay system from Promega (Cat. No. G7941; Lot. 0000168497). The plate was incubated at room temperature in the dark for 5 min under slow shaking conditions. Luciferase activity was obtained by reading with the FlexStation3 from Molecular Devices (luminescence reading, 500 ms). Results are shown as relative light units (RLUs).
- FIG. 3A shows the luciferase activity measured by RLUs for the control experimental conditions after ⁇ 15 hours of stimulation.
- unstimulated cells isotype control FeH3 antibody (Ctrl FeH3) and polyclonal anti-OX40 antibody did not show an increase in RLUs, indicating that the NFkB pathway was not activated.
- FIG. 3A shows the luciferase activity measured by RLUs for the control experimental conditions after ⁇ 15 hours of stimulation.
- isotype control FeH3 antibody Ctrl FeH3 antibody
- polyclonal anti-OX40 antibody did not show an increase in RLUs, indicating that the NFkB pathway was not activated.
- 3B shows luciferase activity measured by RLUs for the anti-OX40 antibody clones tested after ⁇ 15 hours of stimulation. Unstimulated cells and isotype control FeH3 antibody (Ctrl FeH3) are shown as negative controls. Soluble anti-Histidine+purified rhOX40L (rhOX40L+ ⁇ His) is shown as a positive control. As shown in FIG. 3B , all of the OX40 clones showed an increase in RFUs over the negative control values. These results demonstrate that the OX40/HEK293-NFkB-Luc reporter assay worked properly based on internal controls.
- clones 1A11, 1C4, 4D7, 1D9, 5C11, 2B4, 4D9, 3C10 and 1B2 were among the most active.
- a human T cell activation assay was used to identify OX40 clones with agonistic activity.
- a flat-bottom 96-well plate was coated with anti-CD3 (clone OKT3) at 1.5 ⁇ g/ml+(anti-CD28 or anti-OX40 or anti-CD137 clones) at 10 ⁇ g/ml (100 ⁇ l/well final) in PBS 1 ⁇ , overnight at 4° C.
- Anti-CD3 alone and FeD2, an isotype control antibody, were used as negative controls.
- Anti-CD28 was used as a positive control.
- the plate was washed three times with 150 ⁇ l of sterile complete medium per well (RPMI1640+10% FCS+Pen/Strep) under a sterile hood.
- Purified human T cells were plated at 4 ⁇ 10 5 cells/well in complete medium. The plate was incubated at 37° C. for 3 days in a humidified tissue culture incubator.
- the cells were transferred into a V-bottom 96-well plate and washed twice with cold FACS buffer (PBS1 ⁇ +2% FCS), and then stained with PE-labelled anti-human CD25 (clone M-A251) at 5 ⁇ l/well in 70 ⁇ l of FACS buffer for 20 min at 4° C. The cells were spun at 1,500 rpm for 2 min and the supernatant was removed by quickly flipping the plate. Next, the cells were washed with 170 ⁇ l well of FACS buffer. The cells were spun at 1,500 rpm for 2 min and the supernatant was removed by quickly flipping the plate. The washing step was repeated twice. The percentage of CD3+CD25+ activated T cells was measured by flow cytometry. As shown in FIG.
- clones 2B4, 4D7, 2B3, 4G9 and 1B1 showed the most robust agonist activity.
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Abstract
Description
TABLE 1 |
Sequence Listing |
Heavy chain variable | Light chain variable | |
domain regions | domain regions | |
Ox1A11 | EVQLVESGGGLVQTGGSLRLSCAASG | DVVMTQSPSSLSASVGDRVTITCRAS |
FTFSSYWMSWVRQAPGKGLEWVANIK | QGIRNDLHWYQQRPGKAPNLLIYAAS | |
QDGSEKYYVDSVKGRFTISRDNAKNS | SLHSGVPSRFSGSGSGTDFTLTIDSL | |
LYLQMNSLRAEDTAVYYCARDDYYYG | QPEDFATYYCQQANSFPITFGQGTRL | |
MDVWGQGTTVTVSS SEQ ID NO. | EIK SEQ ID NO. 2 | |
1 | ||
Ox1A11 | HC CDR1 | LC CDR1 |
SYWMS | RASQGIRNDLH | |
SEQ ID NO. 49 | SEQ ID NO. 52 | |
HC CDR2 | LC CDR2 | |
NIKQDGSEKYYVDSVKG | AASSLHS | |
SEQ ID NO. 50 | SEQ ID NO. 53 | |
HC CDR3 | LC CDR3 | |
DDYYYGMDV | QQANSFPIT | |
SEQ ID NO. 51 | SEQ ID NO. 54 | |
Ox1B1 | QVQLVQSGAEVKKPGASVKVSCKASG | QSVLTQPPSASGTPGQRVTISCSGSS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | SNIGSNYVYWYQQLPGTAPKLLIYRN | |
PSGGSTSYAQKFQGRVTMTRDTSTST | NQRPSGVPDRFSGSKSGTSASLAISG | |
VYMELSSLRSDDTAVYYCARDPYSSS | LRSEDEADYYCAAWDDSLSGLVFGGG | |
WYGAEYFQHWGQGTLVTVSS SEQ | TKLTVL SEQ ID NO. 4 | |
ID NO. 3 | ||
Ox1B1 | HC CDR1 | LC CDR1 |
SYYMH | SGSSSNIGSNYVY | |
SEQ ID NO. 55 | SEQ ID NO. 58 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | RNNQRPS | |
SEQ ID NO. 56 | SEQ ID NO. 59 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | AAWDDSLSGLV | |
SEQ ID NO. 57 | SEQ ID NO. 60 | |
Ox1B2 | QVQLVQSGAEVKKPGASVKVSCKASG | DIVMTQSPSSLSASVGDRVTITCRAS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | QSISSYLNWYQQKPGKAPKLLIYAAS | |
PSGGSTSYAQKFQGRVTMTRDTSTST | SLQSGVPSRFSGSGSGTDFTLTISSL | |
VYMELSSLRSEDTAVYYCARDYYDSS | QPEDFAIYYCQQNYNTRQVTFGQGTR | |
GYSDYGMDVWGQGTTVTVSS SEQ | LEIK SEQ ID NO. 6 | |
ID NO. 5 | ||
Ox1B2 | HC CDR1 | LC CDR1 |
SYYMH | RASQSISSYLN | |
SEQ ID NO. 61 | SEQ ID NO. 64 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | AASSLQS | |
SEQ ID NO. 62 | SEQ ID NO. 65 | |
HC CDR3 | LC CDR3 | |
DYYDSSGYSDYGMDV | QQNYNTRQVT | |
SEQ ID NO. 63 | SEQ ID NO. 66 | |
Ox1B3 | QVQLVQSGAEVKKPGASVKVSCKTSG | AIQLTQSPSSLSASVGDRVTITCRAS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | QGISSALAWYQQKPGKAPKVLIYDAS | |
PSDGGTRYAQKFQDRVTMTRDMSTST | SLESGVPSRFSGSGSGTDFTLTISSL | |
VYMELSSLRPEDTAVYYCARDLEYIG | QPEDFATYYCQQFNNYPLTFGGGTKV | |
SGSLSWFDPWGQGTLVTVSS SEQ | EIK SEQ ID NO. 8 | |
ID NO. 7 | ||
Ox1B3 | HC CDR1 | LC CDR1 |
GYYLH | RASQGISSALA | |
SEQ ID NO. 67 | SEQ ID NO. 70 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DASSLES | |
SEQ ID NO. 68 | SEQ ID NO. 71 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | QQFNNYPLT | |
SEQ ID NO. 69 | SEQ ID NO. 72 | |
Ox1C4 | EVQLVESGAEVKKPGASVKVSCKTSG | LPVLTQPASVSGSPGQSITISCSGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDFLTYDLVSWYKQQPGKAPKLMIYD | |
PGDGSTRNAQKFEGRVTMTRDTSTST | VNKRPSGVSDRFSGSKSGNTASLTIS | |
VYMELSSLSPEDTAVYYCARDLEYIG | GLQAADEADYYCSSYTSSSTPYVFGT | |
SGSLSWFDPWGQGTLVTVSS SEQ | GTKVTVL SEQ ID NO. 10 | |
ID NO. 9 | ||
Ox1C4 | HC CDR1 | LC CDR1 |
GYYLH | SGTSSDFLTYDLVS | |
SEQ ID NO. 73 | SEQ ID NO. 76 | |
HC CDR2 | LC CDR2 | |
IINPGDGSTRNAQKFEG | DVNKRPS | |
SEQ ID NO. 74 | SEQ ID NO. 77 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYTSSSTPYV | |
SEQ ID NO. 75 | SEQ ID NO. 78 | |
Ox1C5 | QVQLVQSGAEVKKPGASVKVSCKASG | QSVLTQPRSVSGSPGQSVTISCTGTS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | SDGGDYNYVSWYQQHPGQAPKLLIYE | |
PSGGSTSYAQKFQGRVTMTTDTSTST | VSNRPSGVSNRFSGSKSGNTASLTIS | |
AYMELRSLRSDDTAVYYCARDPYSSS | GLQAEDEADYYCSSYTSSSTLVVFGG | |
WYGAEYFQHWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 12 | |
ID NO. 11 | ||
Ox1C5 | HC CDR1 | LC CDR1 |
SYYMH | TGTSSDGGDYNYVS | |
SEQ ID NO. 79 | SEQ ID NO. 82 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | EVSNRPS | |
SEQ ID NO. 80 | SEQ ID NO. 83 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | SSYTSSSTLVV | |
SEQ ID NO. 81 | SEQ ID NO. 84 | |
Ox1D9 | QVQLVQSGAEVKKPGASVKVSCKASG | DVVMTQSPSSLSASVGDRVTITCQAS |
YTFTSYGISWVRQALGQRLEWLGWIN | QDISNYLNWYQQKPGKAPKLLIYDAS | |
AGDGETKYSPKFQGRVTITRDTSAST | NLETGVPSRFSGGGSGTDFTFTISSL | |
AYMDLSGLTSEDTAVYYCARDFLSTM | QPEDIATYYCQQFDNLPYTFGQGTKV | |
DYWGQGTLVTVSS SEQ ID NO. | EIK SEQ ID NO. 14 | |
13 | ||
Ox1D9 | HC CDR1 | LC CDR1 |
SYGIS | QASQDISNYLN | |
SEQ ID NO. 85 | SEQ ID NO. 88 | |
HC CDR2 | LC CDR2 | |
WINAGDGETKYSPKFQG | DASNLET | |
SEQ ID NO. 86 | SEQ ID NO. 89 | |
HC CDR3 | LC CDR3 | |
DFLSTMDY | QQFDNLPYT | |
SEQ ID NO. 87 | SEQ ID NO. 90 | |
Ox1E10 | EVQLVESGAEVKKPGASVKVSCKTSG | QPVLTQPPSASGSPGQSVTISCTGTS |
YTFTGYYLHWVRQAPGQGLQWMGWIN | SDIGGYNYVSWYQQHPGKAPKLLIYE | |
PTSGDTNYAPEYQGRVTMTRDTSIST | VSKRPSGVPARFAGSKSGNTASLTVS | |
AYMELSSLRSDDTAVYYCARGHDYSR | GLQAEDEADYYCSSYAGNNNHVFGTG | |
TPVGAEALDYWGQGTLVTVSS SEQ | TKLTVL SEQ ID NO. 16 | |
ID NO. 15 | ||
Ox1E10 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDIGGYNYVS | |
SEQ ID NO. 91 | SEQ ID NO. 94 | |
HC CDR2 | LC CDR2 | |
WINPTSGDTNYAPEYQG | EVSKRPS | |
SEQ ID NO. 92 | SEQ ID NO. 95 | |
HC CDR3 | LC CDR3 | |
GHDYSRTPVGAEALDY | SSYAGNNNHV | |
SEQ ID NO. 93 | SEQ ID NO. 96 | |
Ox1E7 | QVQLVQSGAEVKKPGASVKVSCKTSG | QSVLTQPASVSGSPGQSITIPCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | NDIGTYNLASWYQHHAGKAPKLIIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | LNHRPSGVSNRFSGYKSDNTAFLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQPEDESNYYCSSYTMNTTPILFGG | |
SGSLSWFDPWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 17 | |
ID NO. 7 | ||
Ox1E7 | HC CDR1 | LC CDR1 |
GYYLH | TGTSNDIGTYNLAS | |
SEQ ID NO. 67 | SEQ ID NO. 97 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DLNHRPS | |
SEQ ID NO. 68 | SEQ ID NO. 98 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYTMNTTPIL | |
SEQ ID NO. 69 | SEQ ID NO. 99 | |
Ox1F2 | QVQLVQSGAEVKKPGASVKVSCKASG | QPVLTQPPSASGTPGQRVTISCSGSS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | SNIGNNFVYWYQQLPGMAPKLLIYKN | |
PSGGSTSYAQKFQGRVTMTRDTSTST | NQRPSGVPDRFSGSKSGTSASLAISG | |
VYMELSSLRSDDTAVYYCARDPYSSS | LRSEDEADYHCAAWDDSLSGHVVFGG | |
WYGAEYFQHWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 18 | |
ID NO. 3 | ||
Ox1F2 | HC CDR1 | LC CDR1 |
SYYMH | SGSSSNIGNNFVY | |
SEQ ID NO. 55 | SEQ ID NO. 100 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | KNNQRPS | |
SEQ ID NO. 56 | SEQ ID NO. 101 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | AAWDDSLSGHVV | |
SEQ ID NO. 57 | SEQ ID NO. 102 | |
Ox1G9 | QVQLVQSGAEVKKPGASVKVSCKTSG | QSVLTQPASVSGSPGQSVTVSCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDIGAYESVSWYQQHPGKGPKLIIYD | |
PSDGSTRNAQKFEGRVTMTRDTSTST | VSSRPSGVSIRFSGSKSGNSASLTIS | |
VYMELSSLSPEDTAVYYCARDLEYIG | GLQAEDEAEYFCSSFTRGSTPYVFGT | |
SGSLSWFDPWGQGTLVTVSS SEQ | GTKVTVL SEQ ID NO. 20 | |
ID NO. 19 | ||
Ox1G9 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDIGAYESVS | |
SEQ ID NO. 103 | SEQ ID NO. 106 | |
HC CDR2 | LC CDR2 | |
IINPSDGSTRNAQKFEG | DVSSRPS | |
SEQ ID NO. 104 | SEQ ID NO. 107 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSFTRGSTPYV | |
SEQ ID NO. 105 | SEQ ID NO. 108 | |
Ox2B12 | QVQLVQSGAEVKKPGASVKVSCKASG | QSVLTQPASVSGSPGQSITISCTGTS |
YTFSNYYMHWVRQAPGQGLEWMGLLN | SDVGAYNYVSWYQQHPGRAPKLMIYD | |
PSGGYTTYAQRFQGRVTMTWDTSTST | VSDRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLTSEDTAVYYCAKDPYSSS | GLQAEDEADYYCSSYTSSSSLYVFGT | |
WYGAEYFQHWGQGTLVTVSS SEQ | GTKVTVL SEQ ID NO. 22 | |
ID NO. 21 | ||
Ox2B12 | HC CDR1 | LC CDR1 |
NYYMH | TGTSSDVGAYNYVS | |
SEQ ID NO. 109 | SEQ ID NO. 112 | |
HC CDR2 | LC CDR2 | |
LLNPSGGYTTYAQRFQG | DVSDRPS | |
SEQ ID NO. 110 | SEQ ID NO. 113 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | SSYTSSSSLYV | |
SEQ ID NO. 111 | SEQ ID NO. 114 | |
Ox2B3 | QVQLVQSGAEVKKPGASVKVSCKTSG | QSVLTQPASVSGSPGQSITISCTGSS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDIGGYNSVSWYQQYPGKAPKLMIHD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VNERPSGISDRFSGSKSGNTASLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQGEDEAEYYCASYSVFSPFLFGRG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TKLTVL SEQ ID NO. 23 | |
ID NO. 7 | ||
Ox2B3 | HC CDR1 | LC CDR1 |
GYYLH | TGSSSDIGGYNSVS | |
SEQ ID NO. 67 | SEQ ID NO. 115 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVNERPS | |
SEQ ID NO. 68 | SEQ ID NO. 116 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | ASYSVFSPFL | |
SEQ ID NO. 69 | SEQ ID NO. 117 | |
Ox2B4 | QMQLVQSGAEVKKPGASVKVSCKTSG | QPVLTQPASVSGSPGQSITISCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDLGAYDYVSWYQQQPGQAPKLIIYD | |
PSDGSTRNAQKFEGRVTMTRDTSTST | VNNRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLSPEDTAVYYCARDLEYIG | GLQAEDEADYYCSSYTSSSTLVYVFG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TGTKVTVL SEQ ID NO. 25 | |
ID NO. 24 | ||
Ox2B4 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDLGAYDYVS | |
SEQ ID NO. 118 | SEQ ID NO. 121 | |
HC CDR2 | LC CDR2 | |
IINPSDGSTRNAQKFEG | DVNNRPS | |
SEQ ID NO. 119 | SEQ ID NO. 122 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYTSSSTLVYV | |
SEQ ID NO. 120 | SEQ ID NO. 123 | |
Ox2B6 | QVQLVQSGAEVKKPGASVKVSCKTSG | LPVLTQPASVSGSPGQSITISCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDVGYYDSVSWYQQYPGKAPKLLIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VSKRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQADDEAEYHCSSYSDSSPFVFGTG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TKVTVL SEQ ID NO. 26 | |
ID NO. 7 | ||
Ox2B6 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDVGYYDSVS | |
SEQ ID NO. 67 | SEQ ID NO. 124 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVSKRPS | |
SEQ ID NO. 68 | SEQ ID NO. 125 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYSDSSPFV | |
SEQ ID NO. 69 | SEQ ID NO. 126 | |
Ox2F2 | QVQLVQSGAEVKKPGASVKVSCKTSG | LPVLTQPASVSGSPGQSITISCTGAS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDVGGYNSVSWYQQHPGKAPKLMIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VSNRPSGISNRFSGSKSGNTASLTVS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQAEDEADYYCSSYAGSNIVYVFGT | |
SGSLSWFDPWGQGTLVTVSS SEQ | GTKVTVL SEQ ID NO. 27 | |
ID NO. 7 | ||
Ox2F2 | HC CDR1 | LC CDR1 |
GYYLH | TGASSDVGGYNSVS | |
SEQ ID NO. 67 | SEQ ID NO. 127 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVSNRPS | |
SEQ ID NO. 68 | SEQ ID NO. 128 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYAGSNIVYV | |
SEQ ID NO. 69 | SEQ ID NO. 129 | |
Ox2G2 | QVQLVQSGAEVKKPGASVKVSCKTSG | QPVLTQPASVSGSPGQSITISCTGTT |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDIGGYNSVSWYQQHPGRAPKLIIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VTYRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQAEDEADYYCSSYTSGNSVYVFGT | |
SGSLSWFDPWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 28 | |
ID NO. 7 | ||
Ox2G2 | HC CDR1 | LC CDR1 |
GYYLH | TGTTSDIGGYNSVS | |
SEQ ID NO. 67 | SEQ ID NO. 130 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVTYRPS | |
SEQ ID NO. 68 | SEQ ID NO. 131 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYTSGNSVYV | |
SEQ ID NO. 69 | SEQ ID NO. 132 | |
Ox3C10 | EVQLVQSGAEVKKPGASVKVSCKASG | EIVLTQSPSSLSASVGDRVTITCRAS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | QDISSALAWYQQKPGEPPNLLIYDAS | |
PSGGSTSYAQKFQGRVTMTRDTSTST | TLEGGVPSRFSGSGSGTDFTLTISSL | |
VYMELSSLRSEDTAVYYCARDFSSWY | QPEDFATYSCQQFRTYPLTFGGGTKL | |
AYGMDVWGQGTTVTVSS SEQ ID | EIK SEQ ID NO. 30 | |
NO. 29 | ||
Ox3C10 | HC CDR1 | LC CDR1 |
SYYMH | RASQDISSALA | |
SEQ ID NO. 133 | SEQ ID NO. 136 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | DASTLEG | |
SEQ ID NO. 134 | SEQ ID NO. 137 | |
HC CDR3 | LC CDR3 | |
DFSSWYAYGMDV | QQFRTYPLT | |
SEQ ID NO. 135 | SEQ ID NO. 138 | |
Ox4A11 | EVQLLESGAEVKKPGASVKVSCKASG | QPVLTQPPSVSAAPGQKVTISCSGSS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | SNIGNNYVSWYQQLPGTAPKLLIYDN | |
PSGGSTSYAQKFQGRVTMTRDTSTST | DKRPSGIPDRFSGSTSGTSATLGIAG | |
VYMELSSLRSEDTAVYYCARSTLWFS | LQTGDEADYYCGTWDSSLGWVFGGGT | |
EFDYWGQGTLVTVSS SEQ ID | KLTVL SEQ ID NO. 32 | |
NO. 31 | ||
Ox4A11 | HC CDR1 | LC CDR1 |
SYYMH | SGSSSNIGNNYVS | |
SEQ ID NO. 139 | SEQ ID NO. 142 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | DNDKRPS | |
SEQ ID NO. 140 | SEQ ID NO. 143 | |
HC CDR3 | LC CDR3 | |
STLWFSEFDY | GTWDSSLGWV | |
SEQ ID NO. 141 | SEQ ID NO. 144 | |
Ox4A12 | QVQLVQSGAEVKKPGASVKVSCKASG | QSVLTQPRSVSGSPGQSVTISCTGTS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | SDGGDYNYVSWYQQHPGQAPKLLIYE | |
PSGGSTSYAQKFQGRVTMTRDTSTST | VSNRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLRSDDTAVYYCARDPYSSS | GLQAEDEADYYCSSYTSSSTLVVFGG | |
WYGAEYFQHWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 33 | |
ID NO. 3 | ||
Ox4A12 | HC CDR1 | LC CDR1 |
SYYMH | TGTSSDGGDYNYVS | |
SEQ ID NO. 55 | SEQ ID NO. 145 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | EVSNRPS | |
SEQ ID NO. 56 | SEQ ID NO. 146 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | SSYTSSSTLVV | |
SEQ ID NO. 57 | SEQ ID NO. 147 | |
Ox4B6 | EVQLVQSGAEVKKPGASVKVSCKASG | EIVLTQSPSSLSASVGDRVTITCRAS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | QDISSALAWYQQKPGEPPNLLIYDAS | |
PSGGSTSYAQKFQGRVTMTRDTSTST | TLEGGVPSRFSGSGSGTDFTLTISSL | |
VYMELSSLRSEDTAVYYCARDFSSWY | QPEDFATYSCQQFRTYPLTFGGGTKL | |
AYGMDVWGQGTTVTVSS SEQ ID | EIK SEQ ID NO. 35 | |
NO. 34 | ||
Ox4B6 | HC CDR1 | LC CDR1 |
SYYMH | RASQDISSALA | |
SEQ ID NO. 148 | SEQ ID NO. 151 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | DASTLEG | |
SEQ ID NO. 149 | SEQ ID NO. 152 | |
HC CDR3 | LC CDR3 | |
DFSSWYAYGMDV | QQFRTYPLT | |
SEQ ID NO. 150 | SEQ ID NO. 153 | |
Ox4D4 | QVQLVQSGAEVKKPGASVKVSCKTSG | LPVLTQPASVSGSPGQSITISCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDVGAYNSVSWYQQRPGKAPKLMIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VIQRPSEVSHRFSGSKSGNTASLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLLPEDEAEYFCGSYAASTTFVFGGG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TKLTVL SEQ ID NO. 36 | |
ID NO. 7 | ||
Ox4D4 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDVGAYNSVS | |
SEQ ID NO. 67 | SEQ ID NO. 154 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVIQRPS | |
SEQ ID NO. 68 | SEQ ID NO. 155 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | GSYAASTTFV | |
SEQ ID NO. 69 | SEQ ID NO. 156 | |
Ox4D7 | QVQLVQSGAEVKKPGASVKVSCKASG | QSVLTQPRSVSGSPGQSVTISCTGTS |
YTFTSYYMHWVRQAPGQGLEWMGIIN | SDGGDYNYVSWYQQHPGQAPKLLIYE | |
PSGGSTSYAQKFQGRVTMTTDTSTST | VSNRPSGVSNRFSGSKSGNTASLTIS | |
AYMELRSLRSDDTAVYYCARDPYSSS | GLQAEDEADYYCSSYTSSSTLVVFGG | |
WYGAEYFQHWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 38 | |
ID NO. 37 | ||
Ox4D7 | HC CDR1 | LC CDR1 |
SYYMH | TGTSSDGGDYNYVS | |
SEQ ID NO. 157 | SEQ ID NO. 160 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | EVSNRPS | |
SEQ ID NO. 158 | SEQ ID NO. 161 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | SSYTSSSTLVV | |
SEQ ID NO. 159 | SEQ ID NO. 162 | |
Ox4D9 | EVQLVQSGAEVKKPGASVKLSCKASG | QPVLTQPPSASGTPGQRVSISCSGSS |
YTFTSYFMHWVRQAPGQGLEWMGIIN | SNIGTNTVNWYQQLPGTAPKLLVYSN | |
PSGGSTSYAQKFQGRLTMTRDTSTST | NQRPSGVPDRFSGSKSGTSASLAISG | |
AYMELRSLRSDDTAVYYCARDPYSSS | LQSEDEADYFCSAWDDSLNGQVFGAG | |
WYGAEYFQHWGQGTLVTVSS SEQ | TKVTVL SEQ ID NO. 40 | |
ID NO. 39 | ||
Ox4D9 | HC CDR1 | LC CDR1 |
YFMH | SGSSSNIGTNTVN | |
SEQ ID NO. 163 | SEQ ID NO. 166 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | SNNQRPS | |
SEQ ID NO. 164 | SEQ ID NO. 167 | |
HC CDR3 | LC CDR3 | |
DPYSSSWYGAEYFQH | SAWDDSLNGQV | |
SEQ ID NO. 165 | SEQ ID NO. 168 | |
Ox4G9 | QVQLVQSGAEVKKPGASVKVSCKTSG | LPVLTQPASVSGSPGQSITISCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDVGYYDSVSWYQQYPGKAPKLLIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VSKRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQADDEAEYHCSSYSDSSPFVFGTG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TKVTVL SEQ ID NO. 41 | |
ID NO. 7 | ||
Ox4G9 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDVGYYDSVS | |
SEQ ID NO. 67 | SEQ ID NO. 169 | |
CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVSKRPS | |
SEQ ID NO. 68 | SEQ ID NO. 170 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYSDSSPFV | |
SEQ ID NO. 69 | SEQ ID NO. 171 | |
Ox4H4 | EVQLVQSGGGLVQPGGSLRLSCAASG | DIVMTQSPSSLSASVGDRVTITCQAS |
FSFSGYDMSWVRQAPGKGLEWVSSIS | QDISNSLNWYQQKPGKAPNLLIYDAS | |
TSGGSTNYADSVNGRFIISRDNSKNT | TLQRGVPSRFSGSGSGTKFTFTISSL | |
LYLQMNSLRTEDTAVYYCAREGSGWY | QPEDIATYYCQQYANLPPITFGQGTR | |
DAGYFDYWGQGTLVTVSS SEQ ID | LEIK SEQ ID NO. 43 | |
NO. 42 | ||
Ox4H4 | HC CDR1 | LC CDR1 |
GYDMS | QASQDISNSLN | |
SEQ ID NO. 172 | SEQ ID NO. 175 | |
HC CDR2 | LC CDR2 | |
SISTSGGSTNYADSVNG | DASTLQR | |
SEQ ID NO. 173 | SEQ ID NO. 176 | |
HC CDR3 | LC CDR3 | |
EGSGWYDAGYFDY | QQYANLPPIT | |
SEQ ID NO. 174 | SEQ ID NO. 177 | |
Ox5B9 | QVQLVQSGAEVKKPGASVKVSCKTSG | LPVLTQPASVSGSPGQSITISCTGTT |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDIGGYNSVSWYQQHPGRAPKLIIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VTYRPSGVSNRFSGSKSGNTASLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQAEDEADYYCSSYTSGNSVYVFGT | |
SGSLSWFDPWGQGTLVTVSS SEQ | GTKLTVL SEQ ID NO. 45 | |
ID NO. 44 | ||
Ox5B9 | HC CDR1 | LC CDR1 |
GYYLH | TGTTSDIGGYNSVS | |
SEQ ID NO. 178 | SEQ ID NO. 181 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVTYRPS | |
SEQ ID NO. 179 | SEQ ID NO. 182 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYTSGNSVYV | |
SEQ ID NO. 180 | SEQ ID NO. 183 | |
Ox5C1 | EVQLVQSGGGLVQPGQSLRLSCTPYG | LPVLTQSPSVSVSPGQTGYMNCYGHE |
FSFNDYGMSWVRQAPGKGLEWLAFVG | LTDKYVSWYQKKPGQSPVLVIYEDTK | |
SKASGGASENVAAVQGRFSFSRDDAK | RPSGIPDRFSGSNSGDTATLTISGTQ | |
GIAYLQLNNLKPEDTGVYFCTRDLGT | ALDEADYYCQAWDSNTVIFGGGTKLT | |
SGPYFFDYWGQGTLVTVSS SEQ | VL SEQ ID NO. 47 | |
ID NO. 46 | ||
Ox5C1 | HC CDR1 | LC CDR1 |
DYGMS | YGHELTDKYVS | |
SEQ ID NO. 184 | SEQ ID NO. 187 | |
HC CDR2 | LC CDR2 | |
FVGSKASGGASENVAAVQG | EDTKRPS | |
SEQ ID NO. 185 | SEQ ID NO. 188 | |
HC CDR3 | LC CDR3 | |
DLGTSGPYFFDY | QAWDSNTVI | |
SEQ ID NO. 186 | SEQ ID NO. 189 | |
Ox5D7 | QVQLVQSGAEVKKPGASVKVSCKTSG | LPVLTQPPSVSAAPGQKVTISCSGSS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SNIGNNYVSWYQQLPGTAPKLLIYDN | |
PSDGGTRYAQKFQDRVTMTRDMSTST | NERPSGIPDRFSGSKSGNTASLTISG | |
VYMELSSLRPEDTAVYYCARDLEYIG | LQAEDEADYYCSSYTDRDTPYVFGGG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TKVTVL SEQ ID NO. 48 | |
ID NO. 7 | ||
Ox5D7 | HC CDR1 | LC CDR1 |
GYYLH | SGSSSNIGNNYVS | |
SEQ ID NO. 67 | SEQ ID NO. 190 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DNNERPS | |
SEQ ID NO. 68 | SEQ ID NO. 191 | |
HC CDR3 | LC CDR3 | |
DLEYIGSGSLSWFDP | SSYTDRDTPYV | |
SEQ ID NO. 69 | SEQ ID NO. 192 | |
Ox4B5 | QMQLVQSGAEVKKPGASVKVSCKASG | DIVMTQSPSSLSASVGDRVTITCQAS |
YTFTNFFMHWVRQAPGQGLEWMGIIN | QDISKYLNWYQQKPGKAPKLLIYDAS | |
PSGGSTSYAQKFQGRVTMTRDTSTST | NLETGVPSRFSGSGSGTDFSFTISNL | |
VYMELSSLRSEDTAVYYCARDRELLW | QPEDIATYYCQQSANLPITFGQGTKV | |
FGELSGAFDIWGQGTMVTVSS | EIK SEQ ID NO. 194 | |
SEQ ID NO. 193 | ||
Ox4B5 | HC CDR1 | LC CDR1 |
NFFMH | QASQDISKYLN | |
SEQ ID NO. 195 | SEQ ID NO. 198 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | DASNLET | |
SEQ ID NO. 196 | SEQ ID NO. 199 | |
HC CDR3 | LC CDR3 | |
DRELLWFGELSGAFDI | QQSANLPIT | |
SEQ ID NO. 197 | SEQ ID NO. 200 | |
Ox2E5 | EVQLVQSGAEVKKPGASVTLSCKASG | QSVLTQPASVSASPGQSITISCTGAS |
HTFTNYYMHWVRQAPGQGLEWMGIIN | SDIGGYDYVSWYQQHSGKAPKLMIYE | |
PGGGGTSYAQKFHDRVAMTRDTSTST | ASKRPSGVSHRFSGSKSGNTASLIIS | |
VYMELSSLRSEDTAVYYCTRGLYSAY | GLQAEDEADYYCSSHTTSSTWVFGGG | |
DSPSDLWGQGTLVTVSS SEQ ID | TKLTVL SEQ ID NO. 202 | |
NO. 201 | ||
Ox2E5 | HC CDR1 | LC CDR1 |
NYYMH | TGASSDIGGYDYVS | |
SEQ ID NO. 203 | SEQ ID NO. 206 | |
HC CDR2 | LC CDR2 | |
IINPGGGGTSYAQKFHD | EASKRPS | |
SEQ ID NO. 204 | SEQ ID NO. 207 | |
HC CDR3 | LC CDR3 | |
GLYSAYDSPSDL | SSHTTSSTWV | |
SEQ ID NO. 205 | SEQ ID NO. 208 | |
Ox2B5 | QVQLVQSGAEVKKPGASVKVSCKASG | DIQMTQSPSSLSASLGDRVTITCRAN |
YTFTSYYMHWVRQAPGQGLEWMGIIN | QSISRYLNWYQHKPGKAPKLLIYAAS | |
PSGGSTSYAQKFQGRVTMTRDTSTST | SLQSGVPSRFSGNGSGTDFTLTISSL | |
VYMELSSLRSEDTAVYYCARDYYDSS | QPEDFATYYCQQSYSTPSITFGQGTR | |
GYSDYGMDVWGQGTTVTVSS SEQ | LEIK SEQ ID NO. 209 | |
ID NO. 5 | ||
Ox2B5 | HC CDR1 | LC CDR1 |
SYYMH | RANQSISRYLN | |
SEQ ID NO. 61 | SEQ ID NO. 210 | |
HC CDR2 | LC CDR2 | |
IINPSGGSTSYAQKFQG | AASSLQS | |
SEQ ID NO. 62 | SEQ ID NO. 211 | |
HC CDR3 | LC CDR3 | |
DYYDSSGYSDYGMDV | QQSYSTPSIT | |
SEQ ID NO. 63 | SEQ ID NO. 212 | |
Ox5C11 | QVQLVQSGAEVKKPGASVKVSCKTSG | NFMLTQPRSVSGSPGQSVTISCTGTS |
YTFTGYYLHWVRQAPGQGLEWMGIIN | SDIGGYSSVSWYQQHPGKAPKLIIYD | |
PSDGGTRYAQKFQDRVTMTRDMSTST | VTERPSGVPDRFSGSKSGDTATLTIS | |
VYMELSSLRPEDTAVYYCARDLEYIG | GLQAEDEADYFCSSYAGVYTYVFGTG | |
SGSLSWFDPWGQGTLVTVSS SEQ | TKVTVL SEQ ID NO. 213 | |
ID NO. 7 | ||
Ox5C11 | HC CDR1 | LC CDR1 |
GYYLH | TGTSSDIGGYSSVS | |
SEQ ID NO. 67 | SEQ ID NO. 214 | |
HC CDR2 | LC CDR2 | |
IINPSDGGTRYAQKFQD | DVTERPS | |
SEQ ID NO. 68 | SEQ ID NO. 215 | |
HC CDR3 | LC CDR3 | |
DLYIGSGSLSWFDP | SSYAGVYTYV | |
SEQ ID NO. 69 | SEQ ID NO. 216 | |
Claims (8)
Priority Applications (1)
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US16/323,968 US10781260B2 (en) | 2016-08-08 | 2017-08-07 | Anti-OX40 binding proteins |
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US201662371993P | 2016-08-08 | 2016-08-08 | |
US16/323,968 US10781260B2 (en) | 2016-08-08 | 2017-08-07 | Anti-OX40 binding proteins |
PCT/US2017/045788 WO2018031490A2 (en) | 2016-08-08 | 2017-08-07 | Anti-ox40 binding proteins |
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PCT/US2017/045788 A-371-Of-International WO2018031490A2 (en) | 2016-08-08 | 2017-08-07 | Anti-ox40 binding proteins |
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US (2) | US10781260B2 (en) |
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US11623962B2 (en) * | 2016-08-08 | 2023-04-11 | Sorrento Therapeutics, Inc. | Anti-OX40 binding proteins |
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US11142579B2 (en) | 2017-12-06 | 2021-10-12 | Sorrento Therapeutics, Inc. | Variant antibodies that bind OX40 |
JP2021519298A (en) | 2018-03-27 | 2021-08-10 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Real-time monitoring of titers using UV signals |
EA202092460A1 (en) * | 2018-05-23 | 2021-03-24 | Бейджин, Лтд. | ANTIBODIES TO OX40 AND METHODS OF APPLICATION |
US20210277135A1 (en) | 2018-07-13 | 2021-09-09 | Bristol-Myers Squibb Company | Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a method of treating a cancer or a solid tumor |
WO2020119789A1 (en) * | 2018-12-14 | 2020-06-18 | Wuxi Biologics (Shanghai) Co., Ltd. | Fully human antibodies against ox40, method for preparing the same, and use thereof |
WO2020172658A1 (en) | 2019-02-24 | 2020-08-27 | Bristol-Myers Squibb Company | Methods of isolating a protein |
EP3973274A1 (en) | 2019-05-23 | 2022-03-30 | Bristol-Myers Squibb Company | Methods of monitoring cell culture media |
CN113045654A (en) * | 2019-12-27 | 2021-06-29 | 南开大学 | anti-OX 40 antibodies and uses thereof |
CN114106173A (en) * | 2020-08-26 | 2022-03-01 | 上海泰槿生物技术有限公司 | anti-OX 40 antibodies, pharmaceutical compositions and uses thereof |
CN114106174A (en) * | 2020-08-27 | 2022-03-01 | 苏州景涞医疗科技有限公司 | Low toxicity anti-OX 40 antibodies, pharmaceutical compositions and uses thereof |
JP2023544410A (en) | 2020-10-05 | 2023-10-23 | ブリストル-マイヤーズ スクイブ カンパニー | Methods for concentrating proteins |
WO2023173011A1 (en) | 2022-03-09 | 2023-09-14 | Bristol-Myers Squibb Company | Transient expression of therapeutic proteins |
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WO2018031490A2 (en) * | 2016-08-08 | 2018-02-15 | Sorrento Therapeutics, Inc. | Anti-ox40 binding proteins |
US11142579B2 (en) * | 2017-12-06 | 2021-10-12 | Sorrento Therapeutics, Inc. | Variant antibodies that bind OX40 |
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2017
- 2017-08-07 WO PCT/US2017/045788 patent/WO2018031490A2/en unknown
- 2017-08-07 EP EP17840109.7A patent/EP3497122A2/en not_active Withdrawn
- 2017-08-07 JP JP2019529138A patent/JP2019526623A/en active Pending
- 2017-08-07 US US16/323,968 patent/US10781260B2/en active Active
- 2017-08-07 CA CA3032952A patent/CA3032952A1/en not_active Abandoned
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2020
- 2020-08-17 US US16/995,573 patent/US11623962B2/en active Active
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US11623962B2 (en) * | 2016-08-08 | 2023-04-11 | Sorrento Therapeutics, Inc. | Anti-OX40 binding proteins |
Also Published As
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JP2019526623A (en) | 2019-09-19 |
WO2018031490A3 (en) | 2018-03-22 |
CA3032952A1 (en) | 2018-02-15 |
US11623962B2 (en) | 2023-04-11 |
US20190177422A1 (en) | 2019-06-13 |
US20200385480A1 (en) | 2020-12-10 |
WO2018031490A2 (en) | 2018-02-15 |
EP3497122A2 (en) | 2019-06-19 |
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